Unlocking the age-old secrets of reward and substance use.

Although substance use is widespread across the lifespan from early adolescence to older adulthood, the prevalence of substance use disorder (SUD) differs between age groups. These age differences in SUD rates necessitate an investigation into how age moderates reward sensitivity, and consequently influences the risks and consequences related to substance use. This theoretical review integrates evidence from the literature to address the dynamic interplay between age and reward in the context of substance use. Overall, increasing evidence demonstrates that age moderates reward sensitivity and underlying reward system neurobiology. Reward sensitivity undergoes a non-linear trajectory across the lifespan. Low levels of reward sensitivity are associated with childhood and late adulthood. In contrast, high levels are associated with early to late adolescence, followed by a decline in the twenties. These fluctuations in reward sensitivity across the lifespan contribute to complex associations with substance use. This lends support to adolescence and young adulthood as vulnerable periods for the risk of subsequent SUD. More empirical research is needed to investigate reward sensitivity during SUD maintenance and recovery. Future research should also involve larger sample sizes and encompass a broader range of age groups, including older adults.

Parameter Space and Potential for Biomarker Development in 25 Years of fMRI Drug Cue Reactivity: A Systematic Review.

Importance: In the last 25 years, functional magnetic resonance imaging drug cue reactivity (FDCR) studies have characterized some core aspects in the neurobiology of drug addiction. However, no FDCR-derived biomarkers have been approved for treatment development or clinical adoption. Traversing this translational gap requires a systematic assessment of the FDCR literature evidence, its heterogeneity, and an evaluation of possible clinical uses of FDCR-derived biomarkers. Objective: To summarize the state of the field of FDCR, assess their potential for biomarker development, and outline a clear process for biomarker qualification to guide future research and validation efforts. Evidence Review: The PubMed and Medline databases were searched for every original FDCR investigation published from database inception until December 2022. Collected data covered study design, participant characteristics, FDCR task design, and whether each study provided evidence that might potentially help develop susceptibility, diagnostic, response, prognostic, predictive, or severity biomarkers for 1 or more addictive disorders. Findings: There were 415 FDCR studies published between 1998 and 2022. Most focused on nicotine (122 [29.6%]), alcohol (120 [29.2%]), or cocaine (46 [11.1%]), and most used visual cues (354 [85.3%]). Together, these studies recruited 19 311 participants, including 13 812 individuals with past or current substance use disorders. Most studies could potentially support biomarker development, including diagnostic (143 [32.7%]), treatment response (141 [32.3%]), severity (84 [19.2%]), prognostic (30 [6.9%]), predictive (25 [5.7%]), monitoring (12 [2.7%]), and susceptibility (2 [0.5%]) biomarkers. A total of 155 interventional studies used FDCR, mostly to investigate pharmacological (67 [43.2%]) or cognitive/behavioral (51 [32.9%]) interventions; 141 studies used FDCR as a response measure, of which 125 (88.7%) reported significant interventional FDCR alterations; and 25 studies used FDCR as an intervention outcome predictor, with 24 (96%) finding significant associations between FDCR markers and treatment outcomes. Conclusions and Relevance: Based on this systematic review and the proposed biomarker development framework, there is a pathway for the development and regulatory qualification of FDCR-based biomarkers of addiction and recovery. Further validation could support the use of FDCR-derived measures, potentially accelerating treatment development and improving diagnostic, prognostic, and predictive clinical judgments.

Sex Difference in Cigarette-Smoking Status and Its Association with Brain Volumes Using Large-Scale Community-Representative Data.

BACKGROUND: Cigarette smoking is believed to accelerate age-related neurodegeneration. Despite significant sex differences in both smoking behaviors and brain structures, the active literature is equivocal in parsing out a sex difference in smoking-associated brain structural changes. OBJECTIVE: The current study examined subcortical and lateral ventricle gray matter (GM) volume differences among smokers, active, past, and never-smokers, stratified by sex. METHODS: The current study data included 1959 Dallas Heart Study (DHS) participants with valid brain imaging data. Stratified by gender, multiple-group comparisons of three cigarette-smoking groups were conducted to test whether there is any cigarette-smoking group differences in GM volumes of the selected regions of interest (ROIs). RESULTS: The largest subcortical GM volumetric loss and enlargement of the lateral ventricle were observed among past smokers for both females and males. However, these observed group differences in GM volumetric changes were statistically significant only among males after adjusting for age and intracranial volumes. CONCLUSIONS: The study findings suggest a sex difference in lifetime-smoking-associated GM volumetric changes, even after controlling for aging and intracranial volumes.

Latent profiles of substance use, early life stress, and attention/externalizing problems and their association with neural correlates of reinforcement learning in adolescents.

BACKGROUND: Adolescent substance use, externalizing and attention problems, and early life stress (ELS) commonly co-occur. These psychopathologies show overlapping neural dysfunction in the form of reduced recruitment of reward processing neuro-circuitries. However, it is unclear to what extent these psychopathologies show common v. different neural dysfunctions as a function of symptom profiles, as no studies have directly compared neural dysfunctions associated with each of these psychopathologies to each other. METHODS: In study 1, a latent profile analysis (LPA) was conducted in a sample of 266 adolescents (aged 13-18, 41.7% female, 58.3% male) from a residential youth care facility and the surrounding community to investigate substance use, externalizing and attention problems, and ELS psychopathologies and their co-presentation. In study 2, we examined a subsample of 174 participants who completed the Passive Avoidance learning task during functional magnetic resonance imaging to examine differential and/or common reward processing neuro-circuitry dysfunctions associated with symptom profiles based on these co-presentations. RESULTS: In study 1, LPA identified profiles of substance use plus rule-breaking behaviors, attention-deficit hyperactivity disorder, and ELS. In study 2, the substance use/rule-breaking profile was associated with reduced recruitment of reward processing and attentional neuro-circuitries during the Passive Avoidance task (p < 0.05, corrected for multiple comparisons). CONCLUSIONS: Findings indicate that there is reduced responsivity of striato-cortical regions when receiving outcomes on an instrumental learning task within a profile of adolescents with substance use and rule-breaking behaviors. Mitigating reward processing dysfunction specifically may represent a potential intervention target for substance-use psychopathologies accompanied by rule-breaking behaviors.

Intersection between social inequality and emotion regulation on emerging adult cannabis use.

Emerging adulthood (EA; ages 18-25) is characterized by socioemotional and neurodevelopmental challenges. Cannabis is a widely used substance among EAs, and hazardous use may increase risk for sustained use patterns and related health consequences. Research shows differential increases in hazardous use by objective as well as subjective measures of social inequality, with more concerning trajectories for youth with greater experiences of social inequality. Learning how to flexibly monitor and modify emotions in proactive ways (i.e., emotion regulation) is a central developmental task navigated during the EA window. Challenges to and with emotion regulation processes can contribute to the emergence of mental health symptoms during EA, including hazardous cannabis use. In this perspective, we highlight emotion dysregulation and social inequality as two critical factors that interact to either buffer against or exacerbate cannabis use during the EA period, noting critical gaps in the literature that merit additional research. We recommend novel methods and longitudinal designs to help clarify how dynamic cognition-emotion interplay predicts trajectories of negative emotional experiences and cannabis use in EA.

Time for a paradigm shift: The adolescent brain in addiction treatment.

OBJECTIVE: One route to improve adolescent addiction treatment outcomes is to use translational approaches to help identify developmental neuroscience mechanisms that undergird active treatment ingredients and advance adolescent behavior change. METHODS: This sample included 163 adolescents (ages 15-19) randomized to motivational interviewing (MI) vs. brief adolescent mindfulness (BAM). Youth completed an fMRI paradigm assessing adolescent brain response to therapist language (complex reflection vs. mindful; complex reflection vs. confront; mindful vs. confront) at pre- (prior to the completion of the full intervention) and post-treatment (at 3-month follow-up) and behavioral measures at 3, 6 and 12 months. RESULTS: Youth in both treatment groups showed significant problem drinking reductions at 3 and 6 months, but MI youth demonstrated significantly better treatment outcomes than BAM youth at 12 months. We observed several significant treatment group differences (MI > BAM) in neural response to therapist language, including at pre-treatment when examining complex reflection vs. mindful, and complex reflection vs. confront (e.g., superior temporal gyrus, lingual gyrus); and at post-treatment when examining mindful vs. confront (e.g., supplementary motor area; middle frontal gyrus). When collapsed across treatment groups (MI + BAM), we observed significant differences by time, with youth showing a pattern of brain change in response to complex reflection vs. mindful, and complex reflection vs. confront (e.g., precuneus; postcentral gyrus). There was no evidence of a significant group × time interaction. However, brain change in response to therapist language (complex reflection vs. confront) in regions such as middle frontal gyrus, was associated with reductions in problem drinking at 12 months. Yet, few treatment group differences were observed. CONCLUSIONS: These data underscore the need to better understand therapist language and it's impact on the developing brain, in order to inform and aggregate the most impactful elements of addiction treatment for future treatment development for adolescents.

A methodological checklist for fMRI drug cue reactivity studies: development and expert consensus.

Cue reactivity is one of the most frequently used paradigms in functional magnetic resonance imaging (fMRI) studies of substance use disorders (SUDs). Although there have been promising results elucidating the neurocognitive mechanisms of SUDs and SUD treatments, the interpretability and reproducibility of these studies is limited by incomplete reporting of participants' characteristics, task design, craving assessment, scanning preparation and analysis decisions in fMRI drug cue reactivity (FDCR) experiments. This hampers clinical translation, not least because systematic review and meta-analysis of published work are difficult. This consensus paper and Delphi study aims to outline the important methodological aspects of FDCR research, present structured recommendations for more comprehensive methods reporting and review the FDCR literature to assess the reporting of items that are deemed important. Forty-five FDCR scientists from around the world participated in this study. First, an initial checklist of items deemed important in FDCR studies was developed by several members of the Enhanced NeuroImaging Genetics through Meta-Analyses (ENIGMA) Addiction working group on the basis of a systematic review. Using a modified Delphi consensus method, all experts were asked to comment on, revise or add items to the initial checklist, and then to rate the importance of each item in subsequent rounds. The reporting status of the items in the final checklist was investigated in 108 recently published FDCR studies identified through a systematic review. By the final round, 38 items reached the consensus threshold and were classified under seven major categories: 'Participants' Characteristics', 'General fMRI Information', 'General Task Information', 'Cue Information', 'Craving Assessment Inside Scanner', 'Craving Assessment Outside Scanner' and 'Pre- and Post-Scanning Considerations'. The review of the 108 FDCR papers revealed significant gaps in the reporting of the items considered important by the experts. For instance, whereas items in the 'General fMRI Information' category were reported in 90.5% of the reviewed papers, items in the 'Pre- and Post-Scanning Considerations' category were reported by only 44.7% of reviewed FDCR studies. Considering the notable and sometimes unexpected gaps in the reporting of items deemed to be important by experts in any FDCR study, the protocols could benefit from the adoption of reporting standards. This checklist, a living document to be updated as the field and its methods advance, can help improve experimental design, reporting and the widespread understanding of the FDCR protocols. This checklist can also provide a sample for developing consensus statements for protocols in other areas of task-based fMRI.

Use of Marijuana: Effect on Brain Health: A Scientific Statement From the American Heart Association.

Marijuana is perceived as a harmless drug, and its recreational use has gained popularity among young individuals. The concentration of active ingredients in recreational formulations has gradually increased over time, and high-potency illicit cannabinomimetics have become available. Thus, the consumption of cannabis in the general population is rising. Data from preclinical models demonstrate that cannabinoid receptors are expressed in high density in areas involved in cognition and behavior, particularly during periods of active neurodevelopment and maturation. In addition, growing evidence highlights the role of endogenous cannabinoid pathways in the regulation of neurotransmitter release, synaptic plasticity, and neurodevelopment. In animal models, exogenous cannabinoids disrupt these important processes and lead to cognitive and behavioral abnormalities. These data correlate with the higher risk of cognitive impairment reported in some observational studies done in humans. It is unclear whether the effect of cannabis on cognition reverts after abstinence. However, this evidence, along with the increased risk of stroke reported in marijuana users, raises concerns about its potential long-term effects on cognitive function. This scientific statement reviews the safety of cannabis use from the perspective of brain health, describes mechanistically how cannabis may cause cognitive dysfunction, and advocates for a more informed health care worker and consumer about the potential for cannabis to adversely affect the brain.

Alcohol and Cannabis Use Disorder Symptom Severity, Conduct Disorder, and Callous-Unemotional Traits and Impairment in Expression Recognition.

Background: Alcohol and cannabis are commonly used by adolescents in the United States. Both alcohol use disorder (AUD) and cannabis use disorder (CUD) have been associated with reduced emotion expression recognition ability. However, this work has primarily occurred in adults and has not considered neuro-cognitive risk factors associated with conduct problems that commonly co-occur with, and precede, substance use. Yet, conduct problems are also associated with reduced emotion expression recognition ability. The current study investigated the extent of negative association between AUD and CUD symptom severity and expression recognition ability over and above any association of expression recognition ability with conduct problems [conduct disorder (CD) diagnostic status]. Methods: In this study, 152 youths aged 12.5-18 years (56 female; 60 diagnosed with CD) completed a rapid presentation morphed intensity facial expression task to investigate the association between relative severity of AUD/CUD and expression recognition ability. Results: Cannabis use disorder identification test (CUDIT) scores were negatively associated with recognition accuracy for higher intensity (particularly sad and fearful) expressions while CD diagnostic status was independently negatively associated with recognition of sad expressions. Alcohol use disorder identification test (AUDIT) scores were not significantly associated with expression recognition ability. Conclusions: These data indicate that relative severity of CUD and CD diagnostic status are statistically independently associated with reduced expression recognition ability. On the basis of these data, we speculate that increased cannabis use during adolescence may exacerbate a neuro-cognitive risk factor for the emergence of aggression and antisocial behavior.

Relationship between behavioral inhibition and approach motivation systems (BIS/BAS) and intrinsic brain network connectivity in adult cannabis users.

Dampened behavioral inhibition and overactive behavioral approach motivation systems (i.e. BIS/BAS) are associated with cannabis use disorder (CUD), although the underlying neural mechanisms of these alterations have not yet been examined. The brain's executive control network (ECN) plays a role in decision-making and is associated with BIS/BAS. In this study, we tested the hypothesis that altered ECN resting-state functional connectivity (rsFC) underlies dysfunctional behavioral inhibition and approach motivation in cannabis users. To that end, we collected resting-state functional magnetic resonance imaging scans in 86 cannabis using adults and 59 non-using adults to examine group differences in the relationship between ECN rsFC and BIS/BAS. Our results showed that BIS was positively correlated with left ECN rsFC in cannabis users, while it was positively correlated with right ECN rsFC in non-users. There was a trend-level moderation effect of group on the association between BIS/BAS and ECN rsFC, showing a weaker association in BIS/BAS and ECN rsFC in cannabis users compared to non-users. An exploratory mediation analysis found that the severity of CUD mediated the relationship between users' BIS scores and left ECN rsFC. These findings suggest that cannabis use may lead to dysregulation in typical ECN functional organization related to BIS/BAS.

Residual Effects of Cannabis Use on Effort-Based Decision-Making.

OBJECTIVE: Acute Δ9-tetrahydrocannabinol (THC) administration in humans (Lawn etal., 2016) and rats (Silveira, Adams, Morena, Hill, & Winstanley, 2016) has been associated with decreased effort allocation that may explain amotivation during acute cannabis intoxication. To date, however, whether residual effects of cannabis use on effort-based decision-making are present and observable in humans have not yet been determined. The goal of this study was to test whether prolonged cannabis use has residual effects on effort-based decision-making in 24-hr abstinent cannabis using adults. METHOD: We evaluated performance on the Effort Expenditure for Reward Task (EEfRT) in 41 adult cannabis users (mean age = 24.63 years, 21 males) and 45 nonusers (mean age = 23.90 years, 19 males). A mixed 2x3x3 ANOVA with age as a covariate was performed to examine the effect of group, probability of winning, and reward amount on EEfRT performance. EEfRT performance was operationalized as % of trials for which the hard (vs. easy) condition was chosen. Pearson's correlations were conducted to test the relationship between EEfRT performance and measures of cannabis use, anhedonia and motivation. RESULTS: We found that cannabis users selected hard trials significantly more than nonusers regardless of win probability or reward level. Frequency of cannabis use was positively correlated with amount of % hard trials chosen. There were no significant correlations between % hard trials chosen, self-reported anhedonia, or motivation. CONCLUSIONS: These results suggest that unlike acute effects, residual effects of cannabis following 24 hrs of abstinence are associated with greater effort allocation during effort-based decision-making.

Are Sweet Dreams Made of These? Understanding the Relationship Between Sleep and Cannabis Use.

Introduction: There is widespread literature on the interaction between cannabis use and sleep, yet the mechanisms that underlie this relationship are not well understood. Several factors lead to inconsistencies in this relationship suggesting a nuanced interaction between cannabis and sleep. An important question that remains to be addressed is the temporal relationship between disrupted sleep and cannabis use. This literature review summarizes the existing literature on the association between disrupted sleep and cannabis toward the goal of addressing the question of the chronology of these reported effects. Materials and Methods: We conducted a review of the literature using PubMed to summarize current knowledge on the association between cannabis use and sleep in humans. Results: We identified 31 studies on the association of cannabis use and sleep. The findings from these studies were mixed. Cannabis was associated with a variety of impacts on sleep ranging from beneficial effects, such as reduced sleep-onset latency, to negative outcomes, such as reduced sleep duration and suppressed rapid eye movement oscillations. The chronology of the interaction of cannabis and sleep was unclear, although much of the current literature focus on factors that modulate how cannabis impairs sleep after initial use. Conclusion: There was sufficient evidence to suggest that cannabis use alters circadian rhythms, and hence, negatively impacts sleep. The current literature is largely from studies utilizing self-report measures of sleep; thus, objective measures of sleep are needed. In addition, although there were no empirical studies on the temporal relationship between cannabis use and sleep, the majority of the literature focused on characterizing sleep impairment after cannabis use.

Alcohol Use Disorder and Cannabis Use Disorder Symptomatology in Adolescents and Aggression: Associations With Recruitment of Neural Regions Implicated in Retaliation.

BACKGROUND: Alcohol and cannabis are commonly used by adolescents in the United States. Both alcohol use disorder (AUD) and cannabis use disorder (CUD) have been associated with an increased risk of aggression. One form of aggression seen during retaliation is reactive aggression to social provocation. This study investigated the association between AUD and CUD symptom severity and recruitment of neural regions implicated in retaliation. METHODS: In this study, 102 youths aged 13-18 years (67 male; 84 in residential care) completed self-report measures of aggression-related constructs and participated in a retaliation task during functional magnetic resonance imaging to investigate the association between relative severity of AUD/CUD and atypical recruitment of regions implicated in retaliation. RESULTS: AUD Identification Test scores were positively associated with irritability and reactive aggression scores. CUD Identification Test scores were positively associated with callous-unemotional traits and both proactive and reactive aggression scores. In functional magnetic resonance imaging analyses, only AUD Identification Test (not CUD Identification Test) scores were associated with an exaggerated recruitment of regions implicated in retaliation (dorsomedial frontal, anterior insula cortices, caudate, and, to a lesser extent, periaqueductal gray). CONCLUSIONS: These data suggest that relative severity of AUD is associated with a disinhibited, exaggerated retaliation response that relates to an increased risk for reactive aggression. Similar findings were not related to severity of CUD.

Individual associations of adolescent alcohol use disorder versus cannabis use disorder symptoms in neural prediction error signaling and the response to novelty.

Two of the most commonly used illegal substances by adolescents are alcohol and cannabis. Alcohol use disorder (AUD) and cannabis use disorder (CUD) are associated with poorer decision-making in adolescents. In adolescents, level of AUD symptomatology has been negatively associated with striatal reward responsivity. However, little work has explored the relationship with striatal reward prediction error (RPE) representation and the extent to which any augmentation of RPE by novel stimuli is impacted. One-hundred fifty-one adolescents participated in the Novelty Task while undergoing functional magnetic resonance imaging (fMRI). In this task, participants learn to choose novel or non-novel stimuli to gain monetary reward. Level of AUD symptomatology was negatively associated with both optimal decision-making and BOLD response modulation by RPE within striatum and regions of prefrontal cortex. The neural alterations in RPE representation were particularly pronounced when participants were exploring novel stimuli. Level of CUD symptomatology moderated the relationship between novelty propensity and RPE representation within inferior parietal lobule and dorsomedial prefrontal cortex. These data expand on an emerging literature investigating individual associations of AUD symptomatology levels versus CUD symptomatology levels and RPE representation during reinforcement processing and provide insight on the role of neuro-computational processes underlying reinforcement learning/decision-making in adolescents.

Alcohol use disorder and cannabis use disorder symptomatology in adolescents is associated with dysfunction in neural processing of future events.

Two of the most commonly used substances by adolescents in the United States are cannabis and alcohol. Cannabis use disorder (CUD) and alcohol use disorder (AUD) are associated with impairments in decision-making processes. One mechanism for impaired decision-making in these individuals is thought to be an inability to adequately represent future events during decision-making. In the current study involving 112 adolescents, we used a comparative optimism task to examine the relationship between relative severity of CUD/AUD (as indexed by the CUD/AUD Identification Tests [CUDIT/AUDIT]) and atypical function within neural systems underlying affect-based neural represenation future events. Greater CUDIT scores were negatively related to responses within subgenual anterior and posterior cingulate cortex when processing high-intensity potential future positive and negative events. There was also a particularly marked negative relationship between CUD symptoms and blood oxygen level-dependent (BOLD) responses within visual and premotor cortices to high-intensity, negatively valenced potential future events. However, AUD symptom severity was not associated with dysfunction within these brain regions. These data indicate that relative risk/severity of CUD is associated with reduced responsiveness to future high-intensity events. This may impair decision-making where future significant consequences should guide response choice.

Cognitive Functioning Related to Binge Alcohol and Cannabis Co-Use in Abstinent Adolescents and Young Adults.

OBJECTIVE: Despite preliminary evidence of unique acute cognitive and psychopharmacological changes attributable to combined alcohol and cannabis use, few studies have investigated more chronic effects of same-day co-use, particularly during neurodevelopmentally sensitive periods. Therefore, relationships between past-month binge alcohol and cannabis co-use and cognitive functioning were examined in adolescents and young adults. METHOD: Data from the Imaging Data in Emerging Adults with Addiction (IDEAA) Consortium were used to assess cognitive functioning in emerging adults with a large range of substance use (n = 232; 15-26 years old) who were abstinent for at least 3 weeks. Multiple regressions assessed cognitive functioning by past-month binge episodes, cannabis use episodes, and same-day co-use, controlling for covariates (e.g., study site, sex, age). RESULTS: After correcting for multiple comparisons, more past-month co-use episodes were related to decreased Ruff 2&7 selective attention accuracy (p = .036). Sex significantly covaried with California Verbal Learning Test-Second Edition initial learning. CONCLUSIONS: Although few significant relationships were found and effect sizes are modest, the persistence of an effect on attention despite a period of sustained abstinence highlights the need to carefully investigate patterns of substance use and potential independent and interactive effects on the developing brain.

Dynamic functional connectivity between nucleus accumbens and the central executive network relates to chronic cannabis use.

The neural mechanisms of drug cue-reactivity regarding the temporal fluctuations of functional connectivity, namely the dynamic connectivity, are sparsely studied. Quantifying the task-modulated variability in dynamic functional connectivity at cue exposure can aid the understanding. We analyzed changes in dynamic connectivity in 54 adult cannabis users and 90 controls during a cannabis cue exposure task. The variability was measured as standard deviation in the (a) connectivity weights of the default mode, the central executive, and the salience networks and two reward loci (amygdalae and nuclei accumbens); and (b) topological indexes of the whole brain (global efficiency, modularity and network resilience). These were compared for the main effects of task conditions and the group (users vs. controls), and correlated with pre- and during-scan subjective craving. The variability of connectivity weights between the central executive network and nuclei accumbens was increased in users throughout the cue exposure task, and, was positively correlated with during-scan craving for cannabis. The variability of modularity was not different by groups, but positively correlated with prescan craving. The variability of dynamic connectivity during cannabis cue exposure task between the central executive network and the nuclei accumbens, and, the level of modularity, seem to relate to the neural underpinning of cannabis use and the subjective craving.

Alcohol Use Disorder, But Not Cannabis Use Disorder, Symptomatology in Adolescents Is Associated With Reduced Differential Responsiveness to Reward Versus Punishment Feedback During Instrumental Learning.

BACKGROUND: The two most commonly used illegal substances by adolescents in the United States are alcohol and cannabis. Alcohol use disorder (AUD) and cannabis use disorder (CUD) have been associated with dysfunction in decision-making processes in adolescents. One potential mechanism for these impairments is thought to be related to abnormalities in reward and punishment processing. However, very little work has directly examined potential differential relationships between AUD and CUD symptom severity and neural dysfunction during decision making in adolescents. METHODS: In the current study, 154 youths participated in a passive avoidance learning task during functional magnetic resonance imaging to investigate the relationship between relative severity of AUD/CUD and dysfunction in processing reward and punishment feedback. RESULTS: Increasing Alcohol Use Disorder Identification Test scores were associated with reduced neural differentiation between reward and punishment feedback within regions of striatum, posterior cingulate cortex, and parietal cortex. However, increasing Cannabis Use Disorder Identification Test scores were not associated with any neural dysfunction during the passive avoidance task. CONCLUSIONS: These data expand on emerging literature that relative severity of AUD is associated with reduced responsivity to rewards in adolescents and that there are differential associations between AUD and CUD symptoms and neurocircuitry dysfunction in the developing adolescent brain.

Binge and Cannabis Co-Use Episodes in Relation to White Matter Integrity in Emerging Adults.

Background: Growing evidence suggests that cannabis and alcohol (and especially binge alcohol drinking) use independently alters neural structure and functioning, particularly during sensitive developmental time periods (e.g., emerging adulthood). However, few studies have investigated the effects of same-day use of these two substances. Here, white matter (WM) integrity was investigated in relation to binge alcohol drinking, cannabis, and same-day binge and cannabis co-use in adolescents and emerging adults. Methods: FreeSurfer's TRACULA was used to assess WM in emerging adults (n=75; 16-26 years old). Timeline Followback calculated past month cannabis use, binge episodes, and same-day cannabis and binge drinking co-use. Multiple regressions investigated WM by past month cannabis, binge, and co-use. Results: Results revealed co-use episodes were related to lower fractional anisotropy (FA), an overall measure of neuronal integrity, in three tracts (left inferior longitudinal fasciculus [ILF], p=0.02; right anterior thalamic radiation [ATR], p=0.01; and left cingulum cingulate gyrus [CCG], p=0.01); and lower axial diffusivity in left ILF (p=0.03). Cannabis use was significantly related to greater FA in left ILF (p=0.005), left ATR (p=0.02), right ATR (p=0.05), left CCG (p=0.006), right CCG (p=0.03), and right superior longitudinal fasciculus parietal (p=0.03). Binge episodes related to greater FA in right ATR (p=0.03). Conclusions: These findings suggest that co-use was associated with lower WM integrity across frontolimbic tracts. In addition, greater FA was related to greater cannabis use across several tracts and binge alcohol use in one tract. Co-users also appeared to be more severe substance users. Future research should investigate the potential independent and interactive effects of these substances on pre-clinical and clinical levels.

Sex-related differences in subjective, but not neural, cue-elicited craving response in heavy cannabis users.

BACKGROUND: Studies indicate that female cannabis users progress through the milestones of cannabis use disorder (CUD) more quickly than male users, likely due to greater subjective craving response in women relative to men. While studies have reported sex-related differences in subjective craving, differences in neural response and the relative contributions of neural and behavioral response remain unclear. METHODS: We examined sex-related differences in neural and behavioral response to cannabis cues and cannabis use measures in 112 heavy cannabis users (54 females). We used principal component analysis to determine the relative contributions of neural and behavioral response and cannabis use measures. RESULTS: We found that principal component (PC) 1, which accounts for the most variance in the dataset, was correlated with neural response to cannabis cues with no differences between male and female users (p = 0.21). PC2, which accounts for the second-most variance, was correlated with subjective craving such that female users exhibited greater subjective craving relative to male users (p = 0.003). We also found that CUD symptoms correlated with both PC1 and PC2, corroborating the relationship between craving and CUD severity. CONCLUSIONS: These results indicate that neural activity primarily underlies response to cannabis cues and that a complex relationship characterizes a convergent neural response and a divergent subjective craving response that differs between the sexes. Accounting for these differences will increase efficacy of treatments through personalized approaches.