Effects of cannabidiol in cannabis flower: Implications for harm reduction.

Using a federally compatible, naturalistic at-home administration procedure, the present study examined the acute effects of three cannabis flower chemovars with different tetrahydrocannabinol (THC) to cannabidiol (CBD) ratios, in order to test whether chemovars with a higher CBD content produce different effects. Participants were randomly assigned to ad libitum administration of one of three chemovars (THC-dominant: 24% THC, 1% CBD; THC+CBD: 9% THC, 10% CBD; CBD-dominant: 1% THC, 23% CBD); 159 regular cannabis users (male = 94, female = 65) were assessed in a mobile pharmacology lab before, immediately after, and 1 h after ad libitum administration of their assigned chemovar. Plasma cannabinoids as well as positive (e.g., high, elation) and negative (e.g., paranoia and anxiety) subjective effects were assessed at each time points. Participants who used the CBD-dominant and THC + CBD chemovars had significantly less THC and more CBD in plasma samples compared to participants who used the THC-dominant chemovar. Further, the THC + CBD chemovar was associated with similar levels of positive subjective effects, but significantly less paranoia and anxiety, as compared to the THC-dominant chemovar. This is one of the first studies to examine the differential effects of various THC to CBD ratios using chemovars that are widely available in state-regulated markets. Individuals using a THC + CBD chemovar had significantly lower plasma THC concentrations and reported less paranoia and anxiety while also reporting similar positive mood effects as compared to individuals using THC only, which is intriguing from a harm reduction perspective. Further research is needed to clarify the harm reduction potential of CBD in cannabis products.

Exploring relationships between alcohol consumption, inflammation, and brain structure in a heavy drinking sample.

BACKGROUND: Chronic alcohol consumption is associated with structural brain changes and increased inflammatory signaling throughout the brain and body. Increased inflammation in the brain has been associated with structural damage. Recent studies have also shown that neurofilament light polypeptide (NfL) is released into the systemic circulation following neuronal damage. Although NfL has thus been proposed as a biomarker for neurodegenerative diseases, its connection to alcohol use disorder has not been explored. For this secondary data analysis, we proposed a conceptual model linking alcohol consumption, the pro-inflammatory cytokine IL-6, brain structure, and NfL in heavy drinking participants. METHODS: Of the 182 individuals enrolled in this study, 81 participants had usable data on gray matter (GM) thickness and 80 had usable data on white matter (WM) diffusivity. A subset of participants had NfL (n = 78) and IL-6 (n = 117) data. An estimate of GM thickness was extracted from middle frontal brain regions using FreeSurfer. Estimated mean WM diffusivity values were extracted from Tract Based Spatial Statistics. NfL and IL-6 were measured in blood. Regression models were used to test individual linkages in the conceptual model. Based on significant regression results, we created a simplified conceptual model, which we tested using path analysis. RESULTS: In regressions, negative relationships emerged between GM and both drinks per drinking day (DPDD) (p = 0.018) and NfL (p = 0.004). A positive relationship emerged between WM diffusivity and DPDD (p = 0.033). IL-6 was not significantly associated with alcohol use, GM or WM. The final path model demonstrated adequate fit to the data and showed significant, negative associations between DPDD and middle frontal gyrus (MFG) thickness, and between MFG thickness and NfL, but the association between DPDD and NfL was not significant. CONCLUSIONS: This is the first study to show that heavy drinking is associated with lower GM thickness and higher WM diffusivity and that lower GM thickness is associated with higher circulating NfL. The analyses also show that the effects of drinking do not involve the pro-inflammatory cytokine IL-6.

Randomized Controlled Trial of an Alcohol-related Sexual Risk Reduction Intervention with Adolescents: The Role of Neurocognitive Activation During Risky Decision-Making.

Justice-involved youth are at a higher risk of negative outcomes from sexual activity and alcohol use relative to their non-justice involved peers. In the current study, we tested the extent to which variability in neurocognitive response (i.e., activation in the right superior parietal lobule; rSPL) during a risky decision-making task moderated the success of a sexual risk reduction intervention. In a cluster randomized trial blocked by gender, justice-involved adolescents (N = 269) first completed a risky decision-making task during a magnetic resonance imaging (MRI) session, then were assigned to an information-only control (GINFO) or sexual risk reduction intervention incorporating alcohol risk reduction content (GPI + GMET) and then re-contacted every three months for one year. Youth in the GPI + GMET intervention reported less sexual risk behavior 12 months after intervention than those in the control. Although neurocognitive activation was associated with sexual risk behavior, it did not moderate intervention outcomes. This risk-reduction intervention appears to work equally well across a range of neurocognitive responses.

Cannabinoids and the Microbiota-Gut-Brain Axis: Emerging Effects of Cannabidiol and Potential Applications to Alcohol Use Disorders.

The endocannabinoid system (ECS) has emerged in recent years as a potential treatment target for alcohol use disorders (AUD). In particular, the nonpsychoactive cannabinoid cannabidiol (CBD) has shown preclinical promise in ameliorating numerous clinical symptoms of AUD. There are several proposed mechanism(s) through which cannabinoids (and CBD in particular) may confer beneficial effects in the context of AUD. First, CBD may directly impact specific brain mechanisms underlying AUD to influence alcohol consumption and the clinical features of AUD. Second, CBD may influence AUD symptoms through its actions across the digestive, immune, and central nervous systems, collectively known as the microbiota-gut-brain axis (MGBA). Notably, emerging work suggests that alcohol and cannabinoids exert opposing effects on the MGBA. Alcohol is linked to immune dysfunction (e.g., chronic systemic inflammation in the brain and periphery) as well as disturbances in gut microbial species (microbiota) and increased intestinal permeability. These MGBA disruptions have been associated with AUD symptoms such as craving and impaired cognitive control. Conversely, existing preclinical data suggest that cannabinoids may confer beneficial effects on the gastrointestinal and immune system, such as reducing intestinal permeability, regulating gut bacteria, and reducing inflammation. Thus, cannabinoids may exert AUD harm-reduction effects, at least in part, through their beneficial actions across the MGBA. This review will provide a brief introduction to the ECS and the MGBA, discuss the effects of cannabinoids (particularly CBD) and alcohol in the brain, gut, and immune system (i.e., across the MGBA), and put forth a theoretical framework to inform future research questions.

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.

Association between the oral microbiome and brain resting state connectivity in smokers.

Recent studies have shown a critical role of the gastrointestinal microbiome in brain and behavior via the complex gut-microbiome-brain axis. However, the influence of the oral microbiome in neurological processes is much less studied, especially in response to the stimuli, such as smoking, within the oral microenvironment. Additionally, given the complex structural and functional networks in brain, our knowledge about the relationship between microbiome and brain function through specific brain circuits is still very limited. In this pilot study, we leveraged next generation sequencing for microbiome and functional neuroimaging technique to enable the delineation of microbiome-brain network links as well as their relationship to cigarette smoking. Thirty smokers and 30 age- and sex-matched nonsmokers were recruited for 16S sequencing of their oral microbial community. Among them, 56 subjects were scanned by resting-state functional magnetic resonance imaging to derive brain functional networks. Statistical analyses were performed to demonstrate the influence of smoking on the oral microbial composition, functional network connectivity, and the associations between microbial shifts and functional network connectivity alternations. Compared to nonsmokers, we found a significant decrease of beta diversity (P = 6 × 10-3) in smokers and identified several classes (Betaproteobacteria, Spirochaetia, Synergistia, and Mollicutes) with significant alterations in microbial abundance. Pathway analysis on the predicted KEGG pathways shows that the microbiota with altered abundance are mainly involved in pathways related to cell processes, DNA repair, immune system, and neurotransmitters signaling. One brain functional network connectivity component was identified to have a significant difference between smokers and nonsmokers (P = 0.032), mainly including connectivity between brain default network and other task-positive networks. This brain functional component was also significantly associated with smoking related microbiota, suggesting a correlated cross-individual pattern between smoking-induced oral microbiome dysbiosis and brain functional connectivity alternation, possibly involving immunological and neurotransmitter signaling pathways. This work is the first attempt to link oral microbiome and brain functional networks, and provides support for future work in characterizing the role of oral microbiome in mediating smoking effects on brain activity.

Cannabis and Health Research: Rapid Progress Requires Innovative Research Designs.

The United States has witnessed enormous changes concerning the acceptance of medicinal and recreational cannabis use. Sixty-three percent of the US population has access to medicinal cannabis markets, which offer increasingly diverse and potent cannabis products. Considering the rapidly changing cultural, political, and legal landscape, the scientific literature does not adequately inform public policy, medical decision making, or harm reduction approaches. The goals of this paper are to (1) investigate the state of cannabis research on medical conditions commonly treated with cannabis, (2) review the barriers that have led to large gaps between cannabis use and available empirical data, and (3) suggest a path forward with new research designs to address these gaps. Thus, we aim to advance a more nuanced understanding of the barriers to cannabis research and suggest innovative research designs necessary for rapid development of a meaningful knowledge base.

DRD2 promoter methylation and measures of alcohol reward: functional activation of reward circuits and clinical severity.

Studies have identified strong associations between D2 receptor binding potential and neural responses to rewarding stimuli and substance use. Thus, D2 receptor perturbations are central to theoretical models of the pathophysiology of substance dependence, and epigenetic changes may represent one of the fundamental molecular mechanisms impacting the effects of alcohol exposure on the brain. We hypothesized that epigenetic alterations in the promoter region of the dopamine D2 receptor (DRD2) gene would be associated with cue-elicited activation of neural reward regions, as well as severity of alcohol use behavior. The current study leveraged functional neuroimaging (fMRI) during an alcohol reward paradigm (n = 383) to test associations among DRD2 promoter methylation in peripheral tissue, signal change in the striatum during the presentation of alcohol cues, and severity of alcohol use disorder (AUD). Controlling for age, DRD2 promoter methylation was positively associated with responses to alcohol cues in the right accumbens (partial r = 0.144, P = 0.005), left putamen (partial r = 0.133, P = 0.009), right putamen (partial r = 0.106, P = 0.039), left caudate (partial r = 0.117, P = 0.022), and right caudate (partial r = 0.133, P = 0.009), suggesting that DRD2 methylation was positively associated with robust activation in the striatum in response to reward cues. DRD2 methylation was also positively associated with clinical metrics of AUD severity. Specifically, controlling for age, DRD2 methylation was associated with Alcohol Use Disorders Identification Test total (partial r = 0.140, P = 0.002); Impaired Control Scale total (partial r = 0.097, P = 0.044) and Alcohol Dependence Scale total (partial r = 0.152, P = 0.001). Thus, DRD2 methylation may be a critical mechanism linking D2 receptors with functional striatal brain changes and clinical severity among alcohol users.

Investigating the Relationships Between Alcohol Consumption, Cannabis Use, and Circulating Cytokines: A Preliminary Analysis.

BACKGROUND: In recent years, human and animal studies have converged to support altered inflammatory signaling as a molecular mechanism underlying the pathophysiology of alcohol use disorders (AUDs). Alcohol binds to receptors on immune cells, triggering signaling pathways that produce pro-inflammatory cytokines. Chronic inflammation is associated with tissue damage, which may contribute to negative effects of AUD. Conversely, cannabis is associated with decreased inflammatory signaling, and animal studies suggest that cannabinoids may impact alcohol-induced inflammation. Thus, the impact of cannabis on inflammation in AUDs in humans warrants examination. METHODS: We explored the relationship between self-reported alcohol and cannabis use and circulating levels of the pro-inflammatory cytokines interleukin 6 (IL-6), IL-8, and IL-1ß in the blood. Among 66 regular drinkers (mean age = 30.08), we examined circulating cytokines and administered questionnaires assessing alcohol consumption and days of cannabis use over the past 90 days. We examined whether alcohol consumption, cannabis use, and gender were associated with changes in circulating cytokines, and whether there was a significant interaction between alcohol and cannabis use predicting blood levels of circulating cytokines. RESULTS: A positive association between alcohol and IL-6 emerged. We also observed a negative association between cannabis and IL-1ß. Follow-up moderation analyses indicated a cannabis by alcohol interaction predicting circulating IL-6, such that cannabis nonusers showed a stronger relationship between alcohol and IL-6 compared to cannabis users. CONCLUSIONS: These preliminary findings suggest that cannabinoid compounds may serve to mitigate inflammation associated with alcohol use. In addition, the present results provide data to inform future investigations, with the goal of ultimately leveraging knowledge of the role of inflammation in AUDs to develop more effective treatments focused on novel immune targets.

Interactions between TLR4 methylation and alcohol consumption on subjective responses to an alcohol infusion.

AIMS: Converging evidence has implicated perturbed inflammatory signaling in alcohol use disorders (AUDs), and both animal and human studies suggest that alcohol-induced inflammatory signaling is mediated by Toll-Like Receptor 4 (TLR4). We previously demonstrated that TLR4 is hypermethylated in subjects with AUD compared to control individuals. Examining the relationship between TLR4 methylation and subjective alcohol responses could shed light on the role of TLR4 in promoting AUDs, thereby highlighting its potential as a treatment target. SHORT SUMMARY: Significant interactions were demonstrated between Toll-like Receptor 4 (TLR4) methylation and human alcohol consumption patterns, such that greater methylation was associated with decreased positive and negative self-reported arousal during an alcohol infusion among light-to-moderate drinkers, but increased self-reported positive arousal and physiological arousal (i.e. systolic blood pressure) among heavy drinkers. METHODS: Latent growth models were used to examine the relationship between TLR4 methylation and subjective responses and physiological measures of arousal during an alcohol infusion across 222 drinkers. RESULTS: We observed significant interactions of TLR4 methylation and alcohol use (drinks per week) on intercepts for self-report and physiological arousal measures. Specifically, light-to-moderate drinkers had positive associations between methylation and stimulation and tension (r's = 0.21-0.24), and heavy drinkers had negative associations (r's = -0.15 to -0.21). There were also significant interaction effects on changes in tension (ß = 0.31, P < 0.01), systolic blood pressure (ß = 0.74, P < 0.01) and marginal effects on stimulation (ß = 0.15, P = 0.07) during the infusion, such that methylation was associated with decreased arousal among light-to-moderate drinkers (r's = -0.12 to -0.25) but stable or increased arousal among heavy drinkers (r's = 0.05-0.19). CONCLUSIONS: Findings suggest that the relationship between TLR4 methylation and subjective and physiological arousal during acute alcohol intoxication depends upon on self-reported alcohol use. These data demonstrate the influence of TLR4 on subjective responses to alcohol, thereby supporting the need for further research on its potential as a pharmacological treatment target.

Default mode network deactivation to smoking cue relative to food cue predicts treatment outcome in nicotine use disorder.

Identifying predictors of treatment outcome for nicotine use disorders (NUDs) may help improve efficacy of established treatments, like varenicline. Brain reactivity to drug stimuli predicts relapse risk in nicotine and other substance use disorders in some studies. Activity in the default mode network (DMN) is affected by drug cues and other palatable cues, but its clinical significance is unclear. In this study, 143 individuals with NUD (male n = 91, ages 18-55 years) received a functional magnetic resonance imaging scan during a visual cue task during which they were presented with a series of smoking-related or food-related video clips prior to randomization to treatment with varenicline (n = 80) or placebo. Group independent components analysis was utilized to isolate the DMN, and temporal sorting was used to calculate the difference between the DMN blood-oxygen-level dependent signal during smoke cues and that during food cues for each individual. Food cues were associated with greater deactivation compared with smoke cues in the DMN. In correcting for baseline smoking and other clinical variables, which have been shown to be related to treatment outcome in previous work, a less positive Smoke - Food difference score predicted greater smoking at 6 and 12 weeks when both treatment groups were combined (P = 0.005, ß = -0.766). An exploratory analysis of executive control and salience networks demonstrated that a more positive Smoke - Food difference score for executive control network predicted a more robust response to varenicline relative to placebo. These findings provide further support to theories that brain reactivity to palatable cues, and in particular in DMN, may have a direct clinical relevance in NUD.

Development, Initial Testing and Challenges of an Ecologically Valid Reward Prediction Error FMRI Task for Alcoholism.

AIMS: To advance translational studies of the role of reward prediction error (PE) in alcohol use disorder, the present study sought to develop and conduct an initial test of an alcohol-specific PE task paradigm using functional magnetic resonance imaging in humans. METHODS: Alcohol dependent or social drinkers received small tastes of their preferred alcohol beverage or control beverage, with preceding visual cues indicating whether alcohol (or water) would be delivered. To assess both positive and negative PE signals, expectancies were systematically violated in both positive (i.e. expecting water and receiving alcohol) and negative (i.e. expecting alcohol and receiving water) directions. Exploratory trial-by-trial analyses were conducted to explore temporal fluctuations of activation within a priori-defined regions of interest that have been implicated in cue reactivity and PE processing. RESULTS: Across the entire sample of participants, positive PE-related brain activation was found in a large cluster comprised of frontal lobe regions, as well as insular cortex, and motor/sensory cortices. Compared to social drinking subjects, alcohol dependent subjects had greater positive PE-related brain activity in left superior parietal lobule, lateral occipital cortex and postcentral gyrus. Exploratory trial-by-trial analyses indicated differences in activation specific to type of taste, mostly at earlier trials. CONCLUSIONS: This task-development oriented pilot study found that PE signaling may not be detected in expected brain regions when image analyses average across all PE trials of the task. Rather, a trial-by-trial analysis approach may help detect sparse, temporally distinct PE signaling in expected reward processing regions. SHORT SUMMARY: This fMRI study of reward prediction error found greater positive prediction error-related activity (i.e. expecting water taste, receiving alcohol taste) in alcohol dependent individuals relative to social drinkers in parietal and occipital cortices. Trial-by-trial analyses may be able to better detect sparse prediction error signaling in expected reward processing regions.

Functional significance of subjective response to alcohol across levels of alcohol exposure.

Pre-clinical neurobiological models of addiction etiology including both the allostatic model and incentive sensitization theory suggest that alcohol consumption among alcohol-dependent (AD) individuals will be dissociated from hedonic reward as positive reinforcement mechanisms wane in later stage dependence. The aims of this study are to test this claim in humans by examining the relationship between dimensions of subjective responses to alcohol (SR) and alcohol craving across levels of alcohol exposure. Non-treatment-seeking drinkers (n = 205) completed an i.v. alcohol challenge (final target breath alcohol concentration = 0.06 g/dl) and reported on SR and craving. Participants were classified as light-to-moderate drinkers (LMD), heavy drinkers (HD) or AD. Analyses examined group differences in SR and craving response magnitude, as well as concurrent and predictive associations between SR domains and craving. At baseline, LMD and AD reported greater stimulation than HD, which carried over post-alcohol administration. However, stimulation was dose-dependently associated with alcohol craving in HD only. Furthermore, lagged models found that stimulation preceded craving among HD only, whereas this hypothesized pattern of results was not observed for craving preceding stimulation. Sedation was also positively associated with craving, yet no group differences were observed. In agreement with the prediction of diminished positive reinforcement in alcohol dependence, this study showed that stimulation/hedonic reward from alcohol did not precede craving in AD, whereas stimulation was dose-dependently associated with and preceded craving among non-dependent HD.

Daily marijuana use is not associated with brain morphometric measures in adolescents or adults.

Recent research has suggested that marijuana use is associated with volumetric and shape differences in subcortical structures, including the nucleus accumbens and amygdala, in a dose-dependent fashion. Replication of such results in well controlled studies is essential to clarify the effects of marijuana. To that end, this retrospective study examined brain morphology in a sample of adult daily marijuana users (n = 29) versus nonusers (n = 29) and a sample of adolescent daily users (n = 50) versus nonusers (n = 50). Groups were matched on a critical confounding variable, alcohol use, to a far greater degree than in previously published studies. We acquired high-resolution MRI scans, and investigated group differences in gray matter using voxel-based morphometry, surface-based morphometry, and shape analysis in structures suggested to be associated with marijuana use, as follows: the nucleus accumbens, amygdala, hippocampus, and cerebellum. No statistically significant differences were found between daily users and nonusers on volume or shape in the regions of interest. Effect sizes suggest that the failure to find differences was not due to a lack of statistical power, but rather was due to the lack of even a modest effect. In sum, the results indicate that, when carefully controlling for alcohol use, gender, age, and other variables, there is no association between marijuana use and standard volumetric or shape measurements of subcortical structures.

Negative and interactive effects of sex, aging, and alcohol abuse on gray matter morphometry.

Chronic alcohol use is associated with declines in gray matter (GM) volume, as is the normal aging process. Less apparent, however, is how the interaction between aging and heavy alcohol use affects changes in GM across the lifespan. There is some evidence that women are more vulnerable to the negative effects of alcohol use on GM than men. In the current study, we examined whether localized GM was related to measures of alcohol use disorder (e.g., AUDIT score) in a large sample (N = 436) of participants, ages 18-55 years, with a range of disease severity, using both voxel-based morphometry (VBM) and surface-based morphometry (SBM). We also explored whether GM associations with alcohol use disorder (AUD) severity are moderated by sex and age. Results showed significant negative associations between AUD severity and GM volume throughout temporal, parietal, frontal, and occipital lobes. Women showed more negative effects of alcohol use than men for cortical thickness in left orbitofrontal cortex, but evidence for increased vulnerability based on sex was limited overall. Similarly, a specific age by alcohol use interaction was observed for volume of right insula, but other regional or global interactions were not statistically supported. However, significant negative associations between heavy alcohol use and GM volumes were observed as early as 18-25 years. These findings support that alcohol has deleterious effects on global and regional GM above and beyond age, and, of particular importance, that regional associations emerge in early adulthood. Hum Brain Mapp 37:2276-2292, 2016. © 2016 Wiley Periodicals, Inc.

An Exploratory Association Study of Alcohol Use Disorder and DNA Methylation.

BACKGROUND: Epigenetic factors, including DNA methylation, play an important role in the etiology of alcohol use disorders (AUDs). Noncandidate-based methylome-wide studies leveraging multiple tissue types are needed in order to identify a set of CpG targets that reliably differentiate AUD patients from controls and strongly correlate across brain tissue and more commonly collected tissue types (e.g., buccal cells). METHODS: Postmortem precuneus brain tissue samples were collected from 49 alcohol-dependent (AD) cases and 47 controls (sample I), and DNA was extracted from precuneus and putamen brain tissue and buccal cells in 24 postmortem subjects (sample II). Methylation levels were analyzed at over 450,000 CpG sites in both samples. CpGs that demonstrated significant methylation differences between cases and controls were advanced for further analysis with the goal of identifying CpGs that also demonstrated consistent methylation correlations across tissue type. RESULTS: In the primary analysis, 244 hypomethylated and 188 hypermethylated CpGs met a priori criteria for both significant methylation differences between cases and controls as well as significant correlation across brain and buccal cell tissue types, employing stringent Bonferroni p-value correction. Many of these CpGs were involved in gene networks related to lipid metabolism, immune response, inflammatory response/disease, and gastro-intestinal disease. CONCLUSIONS: More than 400 CpGs demonstrated differences in methylation between AD cases and controls and showed significant correlation across tissue types. Several genes and pathways (e.g., inflammation and immune functioning) that have been previously associated with AUD were identified in the current analyses.

Reduced executive and default network functional connectivity in cigarette smokers.

Altered functional connectivity has been associated with acute and chronic nicotine use. Connectivity alterations, specifically in the right and left executive control networks (RECN/LECN) and the default mode network (DMN), may contribute to the addiction cycle. The objective of this study was to determine if executive control network (ECN) and DMN connectivity is different between non-smokers and smokers and whether reductions in connectivity are related to chronic cigarette use. The RECN, LECN, and DMN were identified in resting state functional magnetic resonance imaging data in 650 subjects. Analyses tested for group differences in network connectivity strength, controlling for age and alcohol use. There was a significant group effect on LECN and DMN connectivity strength with smokers (n = 452) having lower network strengths than non-smokers (n = 198). Smokers had lower connectivity than non-smokers associated with key network hubs: the dorsolateral prefrontal cortex, and parietal nodes within ECNs. Further, ECN connectivity strength was negatively associated with pack years of cigarette use. Our data suggest that chronic nicotine use negatively impacts functional connectivity within control networks that may contribute to the difficulty smokers have in quitting.

CREB-BDNF pathway influences alcohol cue-elicited activation in drinkers.

Alcohol use disorder (AUD) is suggested to have polygenic risk factors and also exhibits neurological complications, strongly encouraging a translational study to explore the associations between aggregates of genetic variants and brain function alterations related to alcohol use. In this study, we used a semiblind multivariate approach, parallel independent component analysis with multiple references (pICA-MR) to investigate relationships of genome-wide single nucleotide polymorphisms with alcohol cue-elicited brain activations in 315 heavy drinkers, where pICA-MR assesses multiple reference genes for their architecture and functional influences on neurobiological conditions. The genetic component derived from the cAMP-response element-binding protein and -brain derived neurotrophic factor (CREB-BDNF) pathway reference was significantly associated (r = -0.38, P = 3.98 × 10(-12) ) with an imaging component reflecting hyperactivation in precuneus, superior parietal lobule, and posterior cingulate for drinkers with more severe alcohol dependence symptoms. The highlighted brain regions participate in many cognitive processes and have been robustly implicated in craving-related studies. The genetic factor highlighted the CREB and BDNF references, as well as other genes including GRM5, GRM7, GRID1, GRIN2A, PRKCA, and PRKCB. Ingenuity Pathway Analysis indicated that the genetic component was enriched in synaptic plasticity, GABA, and protein kinase A signaling. Collectively, our findings suggest that genetic variations in various neural plasticity and signaling pathways partially explain the variance of precuneus reactivity to alcohol cues which appears to be associated with AUD severity.

Clinical neuroscience of addiction: similarities and differences between alcohol and other drugs.

BACKGROUND: Existing pharmacological treatments for alcohol use disorder (AUD) and other substance use disorders (SUDs) have demonstrated only modest efficacy. Although the field has recently emphasized testing and developing new compounds to treat SUDs, there are numerous challenges inherent to the development of novel medications, and this is particularly true for SUDs. Thus, research to date has tended toward the "repurposing" approach, in which medications developed to treat other mental or physical conditions are tested as SUD treatments. Often, potential treatments are examined across numerous drugs of abuse. Several repurposed medications have shown promise in treating a specific SUD, but few have shown efficacy across multiple SUDs. Examining similarities and differences between AUD and other SUDs may shed light on these findings and offer directions for future research. METHODS: This qualitative review discusses similarities and differences in neural circuitry and molecular mechanism(s) across alcohol and other substances of abuse, and examines studies of pharmacotherapies for AUD and other SUDs. RESULTS: Substances of abuse share numerous molecular targets and involve much of the same neural circuitry, yet compounds tested because they putatively target common mechanisms have rarely indicated therapeutic promise for multiple SUDs. CONCLUSIONS: The lack of treatment efficacy across SUDs may be partially explained by limitations inherent in studying substance users, who comprise a highly heterogeneous population. Alternatively, medications may fail to show efficacy across multiple SUDs due to the fact that the differences between drug mechanisms are more important than their commonalities in terms of influencing treatment response. We suggest that exploring these differences could support novel treatment development, aid in identifying existing medications that may hold promise as treatments for specific SUDs, and ultimately advance translational research efforts.

Factor Structure of Subjective Responses to Alcohol in Light and Heavy Drinkers.

BACKGROUND: Subjective responses (SRs) to alcohol have been implicated in alcoholism etiology, yet less is known about the latent factor structure of alcohol responses. The aim of this study was to examine the factor structure of SR using a battery of self-report measures during a controlled alcohol challenge. METHODS: Nontreatment seeking drinkers (N = 242) completed an intravenous alcohol challenge including the following SR measures: Biphasic Alcohol Effects Scale, Subjective High Assessment Scale, Profile of Mood States, Alcohol Urge Questionnaire, and single items assessing alcohol "Liking" and "Wanting." Ascending limb target breath alcohol concentrations were 0.02, 0.04, and 0.06, and descending limb target was 0.04 g/dl. Exploratory factor analyses were conducted separately on estimates of mean and dose responses on the ascending limb and on descending limb data. To examine the generalizability of this factor structure, these analyses were repeated in heavy drinkers (≥14 drinks/wk for men, ≥7 for women; n = 132) and light drinkers (i.e., nonheavy drinkers; n = 110). RESULTS: In the full sample, a 4-factor solution was supported for ascending limb mean and dose responses and descending limb data representing the following SR domains: Stimulation/Hedonia, Craving/Motivation, Sedation/Motor Intoxication, and Negative Affect. This 4-factor solution was replicated in heavy drinkers. In light drinkers, however, SR was better summarized by a 3-factor solution where ascending mean and descending limb responses consisted of Stimulation/Hedonia, Craving/Motivation, and a general negative valence factor, and dose responses consisted of a general positive valence factor, Sedation/Motor Intoxication, and Negative Affect. CONCLUSIONS: These findings suggest that SR represents a multifaceted construct with consistent factor structure across both ascending and descending limbs. Further, as drinking levels escalate, more defined Craving/Motivation and negative valence dimensions may emerge. Longitudinal studies examining these constructs are needed to further our understanding of SR as potentially sensitive to alcohol-induced neuroadaptation.