Identifying the role of (dis)inhibition in the vicious cycle of substance use through ecological momentary assessment and resting-state fMRI.

Functional inhibition is known to improve treatment outcomes in substance use disorder (SUD), potentially through craving management enabled by underlying cerebral integrity. Whereas treatment is challenged by a multitude of substances that patients often use, no study has yet unraveled if inhibition and related cerebral integrity could prevent relapse from multiples substances, that is, one's primary drug of choice and secondary ones. Individuals with primary alcohol, cannabis, or tobacco use disorders completed intensive Ecological Momentary Assessment (EMA) coupled with resting-state functional MRI (rs-fMRI) to characterize the extent to which inhibition and cerebral substrates interact with craving and use of primary and any substances. Participants were 64 patients with SUD and 35 healthy controls who completed one week EMA using Smartphones to report 5 times daily their craving intensity and substance use and to complete Stroop inhibition testing twice daily. Subsamples of 40 patients with SUD and 34 control individuals underwent rs-fMRI. Mixed Model Analysis revealed that reported use of any substance by SUD individuals predicted later use of any and primary substance, whereas use of the primary substance only predicted higher use of that same substances. Craving and inhibition level independently predicted later use but did not significantly interact. Preserved inhibition performance additionally influenced use indirectly by mediating the link between subsequent uses and by being linked to rs-fMRI connectivity strength in fronto-frontal and cerebello-occipital connections. As hypothesized, preserved inhibition performance, reinforced by the integrity of inhibitory neurofunctional substrates, may partake in breaking an unhealthy substance use pattern for a primary substance but may not generalize to non-target substances or to craving management.

Multi-level prediction of substance use: Interaction of white matter integrity, resting-state connectivity and inhibitory control measured repeatedly in every-day life.

Substance use disorders are characterized by inhibition deficits related to disrupted connectivity in white matter pathways, leading via interaction to difficulties in resisting substance use. By combining neuroimaging with smartphone-based ecological momentary assessment (EMA), we questioned how biomarkers moderate inhibition deficits to predict use. Thus, we aimed to assess white matter integrity interaction with everyday inhibition deficits and related resting-state network connectivity to identify multi-dimensional predictors of substance use. Thirty-eight patients treated for alcohol, cannabis or tobacco use disorder completed 1 week of EMA to report substance use five times and complete Stroop inhibition testing twice daily. Before EMA tracking, participants underwent resting state functional MRI and diffusion tensor imaging (DTI) scanning. Regression analyses were conducted between mean Stroop performances and whole-brain fractional anisotropy (FA) in white matter. Moderation testing was conducted between mean FA within significant clusters as moderator and the link between momentary Stroop performance and use as outcome. Predictions between FA and resting-state connectivity strength in known inhibition-related networks were assessed using mixed modelling. Higher FA values in the anterior corpus callosum and bilateral anterior corona radiata predicted higher mean Stroop performance during the EMA week and stronger functional connectivity in occipital-frontal-cerebellar regions. Integrity in these regions moderated the link between inhibitory control and substance use, whereby stronger inhibition was predictive of the lowest probability of use for the highest FA values. In conclusion, compromised white matter structural integrity in anterior brain systems appears to underlie impairment in inhibitory control functional networks and compromised ability to refrain from substance use.

Association of prenatal substance use disorders with pregnancy and birth outcomes following bariatric surgery.

BACKGROUND/OBJECTIVES: While an increased risk for substance use disorders (SUD) and also for several adverse pregnancy and birth outcomes in patients who have undergone bariatric surgery have been well documented when considered separately, an association between these important risk factors has not been investigated. This study explored the potential dependence of these two bariatric surgery-related risks. SUBJECTS/METHODS: This study was a retrospective cohort study with adult women (18-45) who underwent bariatric surgery between 1996 and 2016 and who gave birth after surgery between 1996 and 2018. The study population consisted of 1849 post-bariatric surgery women with 3010 reported post-surgical births. Subjects with post-surgical, prenatal SUD were identified based on diagnosis codes extracted within the 10 months prior to delivery. Using random-effects logistic regression with retrospective cohort data, preterm birth, low birth weight, macrosomia, Caesarian delivery, congenital anomalies, and neonatal intensive care unit admission were considered as outcomes. RESULTS: About 10% (n = 289) of women had an SUD diagnosis within 10 months prior to child delivery. Women with SUD during pregnancy had significantly more pregnancy and birth complications compared to women without SUD: preterm birth (OR = 2.08, p = 0.03, 95% CI: 1.07-4.03), low birth weight (OR = 3.41, p < 0.01, 95% CI: 1.99-5.84), Caesarian delivery (OR = 9.71, p < 0.01, 95% CI: 2.69-35.05), and neonatal intensive care unit admission (OR = 3.87, p < 0.01, 95% CI: 2.04-7.34). Women with SUD had lower risk for macrosomia than women without SUD (OR = 0.07, p = 0.02, 95% CI: 0.01-0.70). CONCLUSION: Results from this study demonstrated that post-bariatric surgery women who had SUD during pregnancy had significantly more pregnancy- and birth-related complications than post-surgery pregnant women without SUD, despite the reduction in macrosomia. Where possible, greater prenatal surveillance of post-surgery women with SUD should be considered.

A systematic review of the effect of ovarian sex hormones on stimulant use in females.

Stimulant use disorder is associated with significant global health burden. Despite evidence for sex differences in the development and maintenance of stimulant use disorder, few studies have focused on mechanisms underpinning distinct trajectories in females versus males, including the effect of the ovarian sex hormones estrogen and progesterone. This review aimed to identify and synthesise the existing preclinical and clinical literature on the effect of ovarian sex hormones on stimulant consumption in females. A systematic search of peer-reviewed literature identified 1593 articles, screened using the following inclusion criteria: (1) adult female humans or animals, (2) using stimulant drugs, (3) ovarian sex hormones were administered exogenously OR were measured in a validated manner and (4) with stimulant consumption as an outcome measure. A total of 50 studies (3 clinical and 47 preclinical) met inclusion criteria. High-estrogen (low progesterone) phases of the menstrual/estrus cycle were associated with increased stimulant use in preclinical studies, while there were no clinical studies examining estrogen and stimulant consumption. Consistent preclinical evidence supported progesterone use reducing stimulant consumption, which was also identified in one clinical study. The review was limited by inconsistent data reporting across studies and different protocols across preclinical laboratory paradigms. Importantly, almost all studies examined cocaine use, with impact on methamphetamine use a significant gap in the existing evidence. Given the safety and tolerability profile of progesterone, further research is urgently needed to address this gap, to explore the potential therapeutic utility of progesterone as a treatment for stimulant use disorder.

Maternal Exposure and Neonatal Effects of Drugs of Abuse.

The public health crisis of pregnant women being exposed to drugs of abuse and of its impact on their unborn children continues to grow at an alarming rate globally. The state of pregnancy is unique, with physiological changes that can lead to changes in the way drugs are handled by the body in both pharmacokinetics and response. These changes place the pregnant woman, fetus, and newborn infant at risk, as many of these drugs can cross the placenta and into breast milk. The substances most commonly linked to harmful effects include alcohol, tobacco, cannabis, stimulants, and opioids. The pharmacological and toxicological changes caused by in utero exposure or breastfeeding exposure are difficult to study, and the full extent of the mechanisms involved are not fully understood. However, these changes can significantly affect the risks of substance abuse and influence optimal treatment of pregnant women with a substance use disorder. In addition, newborns who were exposed to drugs of abuse in utero can experience withdrawal syndromes. Pharmacological management in infants is used to guide and treat withdrawal symptoms, with the goal being to improve the infant's sleep, eating, and comfort. Several barriers may prevent pregnant women from seeking help for substance use, including stigma and interactions with the legal system. Understanding changes in pharmacology, including pharmacokinetic changes that happen during pregnancy, is essential for anticipating the extent of maternal exposure and neonatal adverse effects.

Association of urinary ketamine and APOA1 levels with bladder dysfunction in ketamine abusers revealed via proteomics and targeted metabolite analyses.

Chronic ketamine abuse is associated with bladder dysfunction and cystitis. However, the effects of ketamine abuse on the urinary proteome profile and the correlations among urinary proteins, urinary ketamine (and metabolites) and clinicopathological features of ketamine-induced bladder dysfunction remain to be established. Here, we recruited 56 ketamine abusers (KA) and 40 age-matched healthy controls (HC) and applied the iTRAQ-based proteomics approach to unravel quantitative changes in the urine proteome profile between the two groups. Many of the differentially regulated proteins are involved in the complement and coagulation cascades and/or fibrotic disease. Among them, a significant increase in APOA1 levels in KA relative to control samples (392.1 ± 59.9 ng/ml vs. 13.7 ± 32.6 ng/ml, p < 0.0001) was detected via ELISA. Moreover, urinary ketamine, norketamine and dehydronorketamine contents (measured via LC-SRM-MS) were found to be positively correlated with overactive bladder syndrome score (OABSS) and APOA1 levels with urinary RBC, WBC, OABSS and numeric pain rating scale in KA. Collectively, our results may aid in developing new molecular tool(s) for management of ketamine-induced bladder dysfunction. Moreover, information regarding the differentially regulated proteins in urine of KA provides valuable clues to establish the molecular mechanisms underlying ketamine-induced cystitis.

Association between functional brain alterations and neuropsychological scales in male chronic smokers using resting-state fMRI.

RATIONALE: Recent studies have demonstrated that cigarette smoking is related to changes in brain structure and function. However, few studies focus on functional brain differences between male chronic smokers and nonsmokers in both local spontaneous activity and whole-brain functional networks. OBJECTIVES: Our study recruited 67 chronic smokers and 43 nonsmokers who underwent functional magnetic resonance imaging (fMRI) scans to investigate functional activity and connectivity alterations in chronic smokers. METHODS: We used the mean fractional amplitude of the low-frequency fluctuation (mfALFF) and mean regional homogeneity (mReHo) methods to investigate resting-state spontaneous activity in chronic smokers and nonsmokers. The graph theoretical analysis (GTA) and network-based statistical (NBS) analysis were also used to investigate functional connectivity alterations. RESULTS: Compared with nonsmokers, chronic smokers exhibited higher activation in the reward system and portions of the prefrontal cortex but lower activation in the default mode networks (DMN) and visual-related regions. In addition, correlation analysis was conducted to assess the associations between neuroimaging findings and the severity of nicotine dependence or expectations of smoking effects. Our results showed that certain brain regions correlated with the Fagerström Test for Nicotine Dependence (FTND), the positive aspect of the Drug Use Disorders Identification Test Extended (DUDIT-E), and the negative aspect of the DUDIT-E, especially in the attentional control networks and hippocampus. The graph theoretical analysis (GTA) results indicated chronic smokers exhibited a trend toward increased assortativity. Our network-based statistical (NBS) analysis revealed reduced functional connections between the subnetwork in the prefrontal cortex, olfactory cortex, angular gyrus, and cingulate gyrus of chronic smokers. CONCLUSIONS: We concluded that chronic smokers have neural adaptations in local spontaneous activity but remain healthy brain functional networks.

Associations between lifetime classic psychedelic use and markers of physical health.

BACKGROUND: In recent years, there has been significant research on the mental health effects of classic psychedelic use, but there is very little evidence on how classic psychedelics might influence physical health. AIMS: The purpose of the present study was to investigate the associations between lifetime classic psychedelic use and markers of physical health. METHODS: Using data from the National Survey on Drug Use and Health (2015-2018) with 171,766 (unweighted) adults aged 18 or above in the United States, the current study examined the associations between lifetime classic psychedelic use and three markers of physical health (self-reported overall health, body mass index, and heart condition and/or cancer in the past 12 months) while controlling for a range of covariates. RESULTS: Respondents who reported having tried a classic psychedelic at least once in their lifetime had significantly higher odds of greater self-reported overall health and significantly lower odds of being overweight or obese versus having a normal weight. The association between lifetime classic psychedelic use and having a heart condition and/or cancer in the past 12 months approached conventional levels of significance, with lower odds of having a heart condition and/or cancer in the past 12 months for respondents who had tried a classic psychedelic at least once. CONCLUSION: The results of the present study suggest that classic psychedelics may be beneficial to physical health. Future research should investigate the causal effects of classic psychedelics on physical health and evaluate possible mechanisms.

Neurotoxic effects of pregabalin dependence on the brain frontal cortex in adult male albino rats.

Pregabalin (PGB) is an analog of the inhibitory neurotransmitter gamma-aminobutyric acid. The currently available evidence favors the misuse and abuse potential of PGB. However, its neurotoxicity remains unclear. Therefore, this study assessed the toxic effects of chronic pregabalin dependence as well as withdrawal on the cortical neurons of the frontal lobe. This study included eighty adult male albino rats which were divided into three groups. Group I (Control) included 40 rats and was further subdivided into two equal subgroups (IA and IB) as negative and positive controls. Group II (PGB-dependent) included 20 rats which received PGB starting with the therapeutic dose (300 mg/day), then the doses were gradually increased until they reached the dependent dose (3400 mg/day) by the end of the first month. Further, the dependent dose was given daily for another 2 months. Group III (PGB withdrawal) included 20 rats which received PGB as described in group II. After that, administration of PGB was stopped and the rats were kept for another one month. By the end of the experiment, all animals were sacrificed by cervical decapitation. The specimens were taken from the frontal cortex for histologic and immunohistochemical staining as well as morphometric analysis. Sections of the frontal cortex of group II showed changes in the form of disturbed architectural pattern of cortical layers, apoptotic cells, weak immunoexpression of Bcl-2 and VEGF as well as moderate-strong immunoexpression of iNOS and nestin. These expressions were significantly different from the control groups, but they were non-significant in comparison with group III. These findings indicate that chronic PGB dependence induces neurotoxic effects mainly in the form of neuronal apoptosis, gliosis, and oxidative stress injury of the frontal cortex. The PGB- induced neurotoxic effects persisted after withdrawal. The influence of these neurotoxic effects and their relevance to the cognitive or neurologic disorders in PGB-dependent individuals warrants further research. Furthermore, it is recommended to quantify the behavioral changes related to PGB dependence as well as withdrawal in future studies.

Nested graft for chronic ulcer in scar tissue after heroin extravasation in a drug addict.

INTRODUCTION: Nested graft is a surgical technique that allows to manage difficult-to-treat medical conditions such as chronic cutaneous ulcers, thanks to the high efficacy it has in reverting the fibroblasts senescence. Because of its peculiar regenerative property, nested graft is a surgical technique suitable also for the treatment of cutaneous ulcers developing on fibrotic scar tissue. CASE REPORT: We reported the case of a 45-year-old man, drug-addict, with a large ulcer on the back of the right forearm in the context of scar fibrotic tissue. This lesion resulted from a previous heroin extravasation treated with a dermo-epidermal skin graft, that was accidentally scratched away by mechanical trauma. After several therapeutic failures with topical medications, we decided to treat the ulcer performing a skin graft using the nested graft technique. No adverse events were reported by the patient during or after the surgery. At the clinical evaluation performed three years later the wound was completely healed. CONCLUSIONS: Nested graft represents a safe and easy-to-use technique that can be successfully used to treat ulcers on scar tissue, ensuring the achievement and the long-term maintenance of optimal resistance and aesthetic results.

Perceived problems with adolescent online gaming: National differences and correlations with substance use.

BACKGROUND: Not much is known about the correlation between gaming problems and substance use across different countries. This paper presents cross-national analyses of different gaming indicators and their relationship to substance use. METHODS: Based on data from the 2015 ESPAD study, differences in the relationship between gaming and substance use across 35 countries were analysed using multi-level logistic regression, using substance use as an individual level predictor, economic wealth as a country-level predictor and a combined problem gaming indicator as the outcome. RESULTS: Multi-level logistic regressions revealed significant correlations between individual substance use and gaming problems, which varied across countries and were moderated by economic wealth. Students who used alcohol, tobacco or cannabis and who lived in high-income countries had a smaller risk of scoring positively on a combined problem gaming indicator than students who used alcohol, tobacco or cannabis and who lived in less prosperous countries. DISCUSSION: Different gaming indicators varied substantially across countries, with self-perceived gaming problems being more common in countries with a low prevalence of gaming. Significant cross-level effects demonstrate the need to take the societal context into account when the relationship between problem gaming and substance use is analysed. Prevention measures need to take the fact into account that patterns of substance use among problem gamers vary across countries.

Adolescent Substance Abuse.

Adolescent substance abuse is America's #1 public health problem as per the National Center on Addiction and Substance Abuse. People are most likely to begin abusing drugs during adolescence, and the longer adolescents defer experimentation, the less likely they are to develop long-term drug abuse problems. The CRAFFT and DAST questionnaires are brief, reliable tools for adolescent substance abuse screening. Health care professionals can help continue low adolescent substance utilization rate by having open conversations with adolescents regarding all substances and medications, including illicit substances.

Blood-based inflammation biomarkers of neurocognitive impairment in people living with HIV.

Inflammation in people living with HIV (PLWH) correlates with severity of HIV-associated neurocognitive disorders. The objective of this study is to identify blood-based markers of neurocognitive function in a demographic balanced cohort of PLWH. Seven neurocognitive domains were evaluated in 121 seropositive Black/African American, Non-Hispanic White, and White Hispanic men and women using computerized assessments. Associations among standardized neurocognitive function and HIV-related parameters, relevant sociodemographic variables, and inflammation-associated cytokines measured in plasma and cellular supernatants were examined using multivariate and univariate regression models. Outlier and covariate analyses were used to identify and normalize for education level, CD4 T cell count, viral load, CNS and drug abuse comorbidities, which could influence biomarker and neurocognitive function associations. Plasma levels of chemokine (C-C motif) ligand (CCL) 8 significantly associated with memory, complex attention, cognitive flexibility, psychomotor speed, executive function, and processing speed. Plasma tissue inhibitor of metalloproteinases 1 associated with the aforementioned domains except memory and processing speed. In addition, plasma interleukin-23 significantly associated with processing speed and executive function. Analysis of peripheral blood cell culture supernatants revealed no significant markers for neurocognitive function. In this cohort, CD4 T cell count and education level also significantly associated with neurocognitive function. All identified inflammatory biomarkers demonstrated a negative correlation to neurocognitive function. These cytokines have known connections to HIV pathophysiology and are potential biomarkers for neurocognitive function in PLWH with promising clinical applications.

Considering Drug-Associated Contexts in Substance Use Disorders and Treatment Development.

Environmental contexts that are reliably associated with the use of pharmacologically active substances are hypothesized to contribute to substance use disorders. In this review, we provide an updated summary of parallel preclinical and human studies that support this hypothesis. Research conducted in rats shows that environmental contexts that are reliably paired with drug use can renew extinguished drug-seeking behavior and amplify responding elicited by discrete, drug-predictive cues. Akin to drug-associated contexts, interoceptive drug stimuli produced by the psychopharmacological effects of drugs can also influence learning and memory processes that play a role in substance use disorders. Findings from human laboratory studies show that drug-associated contexts, including social stimuli, can have profound effects on cue reactivity, drug use, and drug-related cognitive expectancies. This translationally relevant research supports the idea that treatments for substance use disorders could be improved by considering drug-associated contexts as a factor in treatment interventions. We conclude this review with ideas for how to integrate drug-associated contexts into treatment-oriented research based on 4 approaches: pharmacology, brain stimulation, mindfulness-based relapse prevention, and cognitive behavioral group therapy. Throughout, we focus on alcohol- and tobacco-related research, which are two of the most prevalent and commonly misused drugs worldwide for which there are known treatments.

Palliative care for patients with substance use disorder and multiple problems: a qualitative study on experiences of healthcare professionals, volunteers and experts-by-experience.

BACKGROUND: There is little information about how healthcare professionals feel about providing palliative care for patients with a substance use disorder (SUD). Therefore, this study aims to explore: 1) the problems and needs experienced by healthcare professionals, volunteers and experts-by-experience (HCP/VE) during their work with patients with SUD in a palliative care trajectory and; 2) to make suggestions for improvements using the quality of care model by Donabedian (Structure, Process, Outcome). METHODS: A qualitative study was conducted, consisting of six focus group interviews which consisted of HCP/VE working with patients with SUD in a palliative care phase. At the end of the focus group interviews, participants structured and summarized their experiences within a Strengths, Weaknesses, Opportunities and Threats (SWOT) framework. Interview transcripts (other than the SWOT) were analysed by the researchers following procedures from the Grounded Theory Approach ('Grounded Theory Lite'). SWOT-findings were not subjected to in-depth analysis. RESULTS: HCP/VE stated that within the Structure of care, care networks are fragmented and HCP/VE often lack knowledge about patients' multiplicity of problems and the time to unravel these. Communication with this patient group appears limited. The actual care-giving Process requires HCP/VE a lot of creativity and time spent seeking for cooperation with other caregivers and appropriate care settings. The latter is often hindered by stigma. Since no formalized knowledge is available, care-delivery is often exclusively experience-based. Pain-medication is often ineffective due to active substance use. Finally, several Outcomes were brought forward: Firstly, a palliative care phase is often identified only at a late stage. Secondly, education and a (mobile) team of expertise are desired. Thirdly, care for the caregivers themselves is often de-prioritized. CONCLUSIONS: Better integration and collaboration between the different professionals with extensive experience in addiction, palliative and general curative care is imperative to assure good palliative care for patients with SUD. Currently, the resources for this care appear to be insufficient. Development of an educational program and social mapping may be the first steps in improving palliative care for patients with severe SUD.

Adolescence versus adulthood: Differences in basal mesolimbic and nigrostriatal dopamine transmission and response to drugs of abuse.

Epidemiological studies have shown that people who begin experimenting drugs of abuse during adolescence are more likely to develop substance use disorders, and the earliest is the beginning of their use, the greatest is the likelihood to become dependent. Understanding the neurobiological changes increasing adolescent vulnerability to drug use is becoming imperative. Although all neurotransmitter systems undergo relevant developmental changes, dopamine system is of particular interest, given its role in a variety of functions related to reward, motivation, and decision making. Thus, in the present study, we investigated differences in mesolimbic and nigrostriatal dopamine transmission between adolescent (5, 6, 7 weeks of age) and adult rats (10-12 weeks of age), in basal conditions and following drug challenge, by using in vivo brain microdialysis. Although no significant difference between adolescents and adults was observed in dopamine basal levels in the nucleus accumbens (NAc)shell and core, reduced DA levels were found in the dorsolateral striatum (DLS) of early and mid-adolescent rats. Adolescent rats showed greater increase of dopamine in the NAc shell following nicotine (0.4 mg/kg), THC (1.0 mg/kg), and morphine (1.0 mg/kg), in the NAc core following nicotine and morphine, and in the DLS following THC, morphine, and cocaine (10 mg/kg). These results, while adding new insight in the development and functionality of the dopamine system during different stages of adolescence, might provide a neurochemical basis for the greater vulnerability of adolescents to drugs of abuse and for the postulated gateway effect of nicotine and THC toward abuse of other illicit substances.

Regional changes in ∆FosB expression in rat brain following MDMA self-administration predict increased sensitivity to effects of locally infused MDMA.

Repeated exposure to drugs produces a plethora of persistent brain changes, some of which underlie the development of drug addiction. An important objective of addiction research is to identify the brain changes that might mediate the transition from drug use to drug misuse. The persistent accumulation of the transcription factor, ∆FosB, following repeated drug exposure provides a means of achieving this objective. Experiments were conducted on sexually mature male Sprague-Dawley rats. The effects of extensive 3,4-methylenedioxymethamphetamine (MDMA) self-administration on immunohistochemical measurements of ∆FosB accumulation in 12 brain regions was compared with a matched, drug-naive, control group. Other groups were pretreated with MDMA (0.0 or 10.0 mg/kg, ip, once daily for 5 days), and the locomotor-activating effect of MDMA (200 µg/side) microinjected bilaterally into brain regions selected on the basis of the ∆FosB results was subsequently determined. MDMA self-administration significantly increased ∆FosB expression in the nucleus accumbens core, ventromedial and dorsomedial caudate-putamen, anterior cingulate, prelimbic, infralimbic, and orbitofrontal cortex, and both the central and basolateral amygdala, but not in the ventrolateral or dorsolateral caudate-putamen. Increases in the nucleus accumbens shell were substantial but were not significant following statistical correction for multiple comparisons. MDMA pretreatment enhanced MDMA-produced hyperactivity only when administered into the nucleus accumbens or the medial, but not the lateral, caudate-putamen, mirroring the ∆FosB results. These data compare favorably to results following repeated exposure to other drugs of abuse and support the idea of common neuroplastic changes following repeated drug exposure.

DRD2 methylation is associated with executive control network connectivity and severity of alcohol problems among a sample of polysubstance users.

Chronic exposure to alcohol and other drugs of abuse has been associated with deleterious consequences, including functional connectivity deficits within neural networks associated with executive control. Altered functional connectivity within the executive control network (ECN) might underlie the progressive inability to control consumption of alcohol and other drugs as substance use disorders progress. Genetic and epigenetic factors have been associated with substance use disorders (SUDs). For example, dopamine receptor 2 (DRD2) functioning has been associated with alcohol use disorder (AUD) and related phenotypes, including correlates of executive functioning. The present study aims to explore the relationship between a continuous measure of alcohol-related problems, epigenetic markers (methylation) within the DRD2 gene, and functional connectivity within the ECN among a sample of polysubstance users. A community sample of 658 subjects, whose consumption of alcohol, nicotine, and cannabis span across a spectrum of quantity and frequency of use, were obtained across previous studies in polysubstance using populations. Resting state functional magnetic resonance imaging was analyzed to identify intrinsic connectivity networks using a priori regions of interest. Methylation measurement of functionally relevant sites within the DRD2 gene was achieved via pyrosequencing. Regression-based models, including mediation and moderation models, tested the association between DRD2 methylation, functional connectivity within intrinsic neural networks (including the ECN), and severity of alcohol problems. Results suggest that average DRD2 methylation was negatively associated with right ECN (RECN) and left ECN (LECN) connectivity, but not associated with other networks tested, and DRD2 methylation was significantly associated with alcohol problems severity. Mediation models were not supported, although moderation models suggested that connectivity between edges within the RECN moderated the relationship between DRD2 methylation and AUD severity. Results support a theoretical model in which epigenetic factors are associated with neurobiological correlates of alcohol consumption among a sample of polysubstance users.

Health risk behaviours and allostatic load: A systematic review.

Health risk behaviours (HRB) across the lifespan have been associated with higher cumulative physiological burden as measured by allostatic load (AL). This study examines the contribution of HRB and their effects on multisystem biological risk associated with morbidity and early mortality. We systematically reviewed the literature to assess the links between HRB and AL. Twenty-six eligible human studies were included in our assessment of the current literature investigating the association of different HRB that included overeating/obesity, alcohol, smoking, drug use, physical inactivity and sleep impairments in relation to AL. We found that 50 % of obesity and substance abuse, 75 % of sleep and 62.5 % of combined HRB studies showed a significant association with AL. Lifestyle coping behaviours therefore have a significant contribution to AL. This study is among the first to explore multiple domains of HRB in relation to AL. Further research should focus on evaluating lifestyle factors that adapt HRB as a strategy to cope with chronic stress to help decrease AL and resulting long-term negative health consequences.