Rethinking Substance Use as Social History: Charting a Way Forward.

Physicians have traditionally asked about substance use within the Social History section of the consultation note. Drawing on social science theory and using the authors' own experiences as generalists and addiction scholars, we consider the possible unintended harms associated with this approach. The inclusion of the substance use history within the Social History reproduces the discourse of substance use disorders as "life-style choices" rather than medical conditions, and reinforces stigma among healthcare workers through the attribution of personal responsibility for complications associated with problematic substance use. The ongoing placement of the substance use history within the Social History may lead to a failure to diagnose and make appropriate management plans for clients with substance use disorders. These missed opportunities may include inadequate withdrawal management leading to discharge before medically advised, insufficient use of evidence-based pharmacotherapy and psychotherapy, polypharmacy, medical complications, and repeated admissions to hospital. We argue instead that the Substance Use History should be a stand-alone section within the consultation note. This new section would reduce the invisibility of substance use disorders within our medical systems and model that these chronic medical conditions are amenable to prevention, treatment and harm reduction through the application of evidence-based practices.

Neural responses to reward, threat, and emotion regulation and transition to hazardous alcohol use.

AIMS: Reward processing and regulation of emotions are thought to impact the development of addictive behaviors. In this study, we aimed to determine whether neural responses during reward anticipation, threat appraisal, emotion reactivity, and cognitive reappraisal predicted the transition from low-level to hazardous alcohol use over a 12-month period. METHODS: Seventy-eight individuals aged 18-22 with low-level alcohol use [i.e. Alcohol Use Disorder Identification Test (AUDIT) score <7] at baseline were enrolled. They completed reward-based and emotion regulation tasks during magnetic resonance imaging to examine reward anticipation, emotional reactivity, cognitive reappraisal, and threat anticipation (in the nucleus accumbens, amygdala, superior frontal gyrus, and insula, respectively). Participants completed self-report measures at 3-, 6-, 9-, and 12-month follow-up time points to determine if they transitioned to hazardous use (as defined by AUDIT scores ≥8). RESULTS: Of the 57 participants who completed follow-up, 14 (24.6%) transitioned to hazardous alcohol use. Higher baseline AUDIT scores were associated with greater odds of transitioning to hazardous use (odds ratio = 1.73, 95% confidence interval 1.13-2.66, P = .005). Brain activation to reward, threat, and emotion regulation was not associated with alcohol use. Of the neural variables, the amygdala response to negative imagery was numerically larger in young adults who transitioned to hazardous use (g = 0.31), but this effect was not significant. CONCLUSIONS: Baseline drinking levels were significantly associated with the transition to hazardous alcohol use. Studies with larger samples and longer follow-up should test whether the amygdala response to negative emotional imagery can be used to indicate a future transition to hazardous alcohol use.

The effects of acute alcohol administration on circulating endocannabinoid levels in humans.

Several lines of evidence suggest that endocannabinoid signalling may influence alcohol consumption. Preclinical studies have found that pharmacological blockade of cannabinoid receptor 1 leads to reductions in alcohol intake. Furthermore, variations in endocannabinoid metabolism between individuals may be associated with the presence and severity of alcohol use disorder. However, little is known about the acute effects of alcohol on the endocannabinoid system in humans. In this study, we evaluated the effect of acute alcohol administration on circulating endocannabinoid levels by analysing data from two highly-controlled alcohol administration experiments. In the first within-subjects experiment, 47 healthy participants were randomized to receive alcohol and placebo in a counterbalanced order. Alcohol was administered using an intravenous clamping procedure such that each participant attained a nearly identical breath alcohol concentration of 0.05%, maintained over 3 h. In the second experiment, 23 healthy participants self-administered alcohol intravenously; participants had control over their exposure throughout the paradigm. In both experiments, circulating concentrations of two endocannabinoids, N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG), were measured at baseline and following alcohol exposure. During the intravenous clamping procedure, acute alcohol administration reduced circulating AEA but not 2-AG levels when compared to placebo. This finding was confirmed in the self-administration paradigm, where alcohol reduced AEA levels in an exposure-dependent manner. Future studies should seek to determine whether alcohol administration has similar effects on brain endocannabinoid signalling. An improved understanding of the bidirectional relationship between endocannabinoid signalling and alcohol intake may deepen our understanding of the aetiology and repercussions of alcohol use disorder.

High-risk social drinkers and heavy drinkers display similar rates of alcohol consumption.

Alcohol consumption is often assessed over weeks to months, but few attempts have been made to characterize alcohol consumption rates at the level of an individual drinking session. Here, we aimed to compare the rate of alcohol consumption in social drinkers at high risk for alcohol use disorder (AUD) and heavy drinkers. One hundred and sixty social drinkers and 48 heavy drinkers participated in an alcohol self-administration study. Social drinkers were classified as low risk or high risk for AUD based on sex, impulsivity, and family history of alcoholism. Participants received a priming dose of intravenous alcohol to assess alcohol-induced craving and completed a 125-minute intravenous alcohol self-administration session to assess rate of achieving a binge-level exposure (blood alcohol concentration greater than or equal to 80 mg%). There were no differences between rates of binging in high-risk and heavy drinkers (hazard ratio = 0.87; 95% CI, 0.48-1.56). Heavy drinkers reported higher levels of craving than high-risk and low-risk drinkers at baseline. However, following a priming dose of alcohol, there were no longer differences in craving between high-risk and heavy drinkers. These results indicate that high-risk social drinkers demonstrate binging behavior that is similar to heavy drinkers, which may be driven by alcohol-induced craving. Prospective studies are needed to elucidate whether these patterns of craving and consumption in high-risk social drinkers are predictive of future AUD.

Randomized Clinical Trials Investigating Innovative Interventions for Smoking Cessation in the Last Decade.

Every year, billions of dollars are spent treating smoking and related conditions, yet smoking-related morbidity and mortality continue to rise. There are currently only three FDA-approved medications for smoking cessation: nicotine replacement therapy, bupropion, and varenicline. Although these medications increase abstinence rates, most individuals relapse following treatment. This chapter reviews clinical trials published within the past 10 years investigating novel smoking cessation pharmacotherapies. Among these pharmacotherapies, some showed promising results, such as cytisine and endocannabinoid modulators, whereas others failed to produce significant effects. More research is needed to develop drugs that produce higher rates of long-term abstinence and to determine which subgroups of patients benefit from a given treatment.

Endocannabinoid signaling in psychiatric disorders: a review of positron emission tomography studies.

Endocannabinoid signaling is implicated in an array of psychopathologies ranging from anxiety to psychosis and addiction. In recent years, radiotracers targeting the endocannabinoid system have been used in positron emission tomography (PET) studies to determine whether individuals with psychiatric disorders display altered endocannabinoid signaling. We comprehensively reviewed PET studies examining differences in endocannabinoid signaling between individuals with psychiatric illness and healthy controls. Published studies evaluated individuals with five psychiatric disorders: cannabis use disorder, alcohol use disorder, schizophrenia, post-traumatic stress disorder, and eating disorders. Most studies employed radiotracers targeting cannabinoid receptor 1 (CB1). Cannabis users consistently demonstrated decreased CB1 binding compared to controls, with normalization following short periods of abstinence. Findings in those with alcohol use disorder and schizophrenia were less consistent, with some studies demonstrating increased CB1 binding and others demonstrating decreased CB1 binding. Evidence of aberrant CB1 binding was also found in individuals with anorexia nervosa and post-traumatic stress disorder, but limited data have been published to date. Thus, existing evidence suggests that alterations in endocannabinoid signaling are present in a range of psychiatric disorders. Although recent efforts have largely focused on evaluating CB1 binding, the synthesis of new radiotracers targeting enzymes involved in endocannabinoid degradation, such as fatty acid amide hydrolase, will allow for other facets of endocannabinoid signaling to be evaluated in future studies.

Emotion Recognition Biases in Alcohol Use Disorder.

BACKGROUND: Alcohol use disorder (AUD) has been associated with impairments in cognitive and emotional function, including difficulty identifying emotional facial expressions. However, it is unclear whether these deficits are associated with alcohol consumption or related anxious and depressive symptoms. METHODS: We compared the recognition of emotional faces expressing happiness, surprise, sadness, fear, anger, and disgust in 19 AUD participants and 19 healthy volunteers using the Cambridge Neuropsychological Test Automated Battery Emotion Recognition Task. We analyzed group differences in response latency, accuracy, and misidentification patterns (as defined by the tendency to mislabel facial expressions as exhibiting specific emotions). To assess whether misidentification patterns were associated with drinking severity, we also examined associations with alcohol consumption over the past 90 days. RESULTS: There were no differences in response latency or accuracy between groups. However, there were group differences in misidentification patterns. While controls tended to misidentify emotional expressions as happy, those with AUD tended to misidentify expressions as angry or disgusted. In AUD participants, the degree to which individuals were biased toward anger or disgust was positively correlated with the number of drinks they consumed in the past 90 days but was not associated with depression or anxiety scores. CONCLUSIONS: Our findings suggest that individuals with AUD have a bias toward misidentifying emotional facial expressions as hostile, which is not mediated by associated mood changes. This provides further evidence of disrupted social cognition in AUD.

Severity of alcohol dependence is associated with the fatty acid amide hydrolase Pro129Thr missense variant.

The endocannabinoid system plays an important role in reward and addiction. One of the two main endocannabinoid neurotransmitters, anandamide, is metabolized by fatty acid amide hydrolase, an enzyme with a functional genetic polymorphism (FAAH Pro129Thr, rs324420). The Thr129 allele has been linked to problem drug and alcohol use, but the association has not been widely replicated and may be stronger for clinical measures of severity rather than categorical diagnosis. In the present study, we sought to determine whether the Thr129 allele was associated with both alcohol dependence (AD) diagnosis and severity in a sample of 1434 European American and African American individuals, 952 of whom were diagnosed with lifetime AD. Participants were genotyped for FAAH rs324420, and ancestry was determined via a genome-wide panel of ancestry informative markers. Subjects participated in Structured Clinical Interviews for psychiatric disorders and 90-day Timeline Followback interviews to assess recent alcohol use. European American participants with current AD had a higher Thr129 allele frequency than non-dependent controls. In European Americans with lifetime AD, there were significantly different distributions of drinking days and binge drinking days between the two genotype groups, with Thr129 carriers reporting a median of 10 fewer abstinent days and 13 more binge drinking days than Pro129/Pro129 homozygotes. In African American participants, there were no significant differences between Thr129 allele frequency in cases and controls and no significant differences in measures of AD severity by genotype. These findings provide evidence that the Pro129Thr missense variant is associated with AD severity in European Americans.

Neuromodulation for Cannabis Use: A Scoping Review.

This scoping review explores the use of neuromodulation techniques in individuals with cannabis use. Our goal was to determine whether cannabis use alters cortical excitation and inhibition in the context of neuromodulation and to determine whether neuromodulation affects craving and cannabis use patterns. A systematic search was conducted using PubMed, OVID Medline, and PsycINFO from inception to 20 December 2022. Our review identified ten relevant studies, eight of which used Transcranial Magnetic Stimulation (TMS), while two employed Transcranial Direct Current Stimulation (tDCS). Findings from TMS studies suggest that cannabis users exhibit altered cortical inhibition, with decreased short interval intracortical inhibition (SICI) compared to non-users. Single sessions of rTMS did not have any impact on cannabis craving. By contrast, two studies found that multiple sessions of rTMS reduced cannabis use, but these changes did not meet the threshold for statistical significance and both studies were limited by small sample sizes. The two included tDCS studies found contradictory results, with one showing reduced cannabis craving with active treatment and another showing no effect of active treatment on craving compared to sham. Future studies should further explore the effects of multiple treatment sessions and different neuromodulation modalities.

Alcohol Use Disorder and Chronic Pain: An Overlooked Epidemic.

Alcohol use disorder (AUD) and chronic pain disorders are pervasive, multifaceted medical conditions that often co-occur. However, their comorbidity is often overlooked, despite its prevalence and clinical relevance. Individuals with AUD are more likely to experience chronic pain than the general population. Conversely, individuals with chronic pain commonly alleviate their pain with alcohol, which may escalate into AUD. This narrative review discusses the intricate relationship between AUD and chronic pain. Based on the literature available, the authors present a theoretical model explaining the reciprocal relationship between AUD and chronic pain across alcohol intoxication and withdrawal. They propose that the use of alcohol for analgesia rapidly gives way to acute tolerance, triggering the need for higher levels of alcohol consumption. Attempts at abstinence lead to alcohol withdrawal syndrome and hyperalgesia, increasing the risk of relapse. Chronic neurobiological changes lead to preoccupation with pain and cravings for alcohol, further entrenching both conditions. To stimulate research in this area, the authors review methodologies to improve the assessment of pain in AUD studies, including self-report and psychophysical methods. Further, they discuss pharmacotherapies and psychotherapies that may target both conditions, potentially improving both AUD and chronic pain outcomes simultaneously. Finally, the authors emphasize the need to manage both conditions concurrently, and encourage both the scientific community and clinicians to ensure that these intertwined conditions are not overlooked given their clinical significance.

Paramagnetic titanium(III) and zirconium(III) metallocene complexes as precatalysts for the dehydrocoupling/dehydrogenation of amine-boranes.

Complexes of Group 4 metallocenes in the +3 oxidation state and amidoborane or phosphidoborane function as efficient precatalysts for the dehydrocoupling/dehydrogenation of amine-boranes, such as Me(2) NH⋅BH(3). Such Ti(III) -amidoborane complexes are generated in [Cp(2)Ti]-catalyzed amine-borane dehydrocoupling reactions, for which diamagnetic M(II) and M(IV) species have been previously postulated as precatalysts and intermediates.

Delay discounting and family history of psychopathology in children ages 9-11.

Delay discounting is a tendency to devalue delayed rewards compared to immediate rewards. Evidence suggests that steeper delay discounting is associated with psychiatric disorders across diagnostic categories, but it is unclear whether steeper delay discounting is a risk factor for these disorders. We examined whether children at higher risk for psychiatric disorders, based on family history, would demonstrate steeper delay discounting behavior using data from the Adolescent Brain Cognitive Development (ABCD) study, a nationally representative sample of 11,878 children. We looked at associations between delay discounting behavior and family history of alcohol problems, drug problems, depression, mania, schizophrenia, and suicidal behavior. Correlations between family history of psychopathology and delay discounting behavior were small, ranging from ρ = - 0.02 to 0.04. In mixed effects models controlled for sociodemographic factors, family history of psychopathology was not associated with steeper delay discounting behavior. Sociodemographic factors played a larger role in predicting delay discounting behavior than family history of psychopathology. These results do not support the hypothesis that children with greater risk for psychopathology display steeper delay discounting behavior.

Emotion regulation in substance use disorders: a systematic review and meta-analysis.

BACKGROUND AND AIMS: The ability to regulate emotions effectively has been associated with resilience to psychopathology. Individuals with substance use disorders (SUDs) have been shown to have higher levels of negative emotionality, with some evidence suggesting impairment in emotion regulation compared with individuals without SUDs. However, no previous attempt has been made to systematically review the literature to assess the magnitude of this difference. We aimed to assess the association between SUD diagnosis and emotion regulation as measured by the Difficulties in Emotion Regulation Scale (DERS) and Emotion Regulation Questionnaire (ERQ) through a systematic review and meta-analysis of existing findings. METHODS: The systematic review was conducted using PubMed, PsycINFO and Embase. We examined cross-sectional studies that compared a SUD group with a control group and measured emotion regulation using the DERS or the ERQ. The primary analysis focused on papers using the DERS, as this was the predominant instrument in the literature. RESULTS: Twenty-two studies met our primary analysis criteria, representing 1936 individuals with a SUD and 1567 controls. Individuals with SUDs relative to controls had significantly greater DERS scores, with a mean difference of 21.44 [95% confidence interval (CI) = 16.49-26.40, P < 0.001] and Hedges' g = 1.05 (95% CI = 0.86-1.24, P < 0.001). The difference was robust, remaining significant after removing outliers and studies with high risk of bias. Individuals with SUDs demonstrated poorer emotion regulation on each subscale of the DERS, with the largest deficits in the Strategies and Impulse subscales. The ERQ analysis revealed greater use of expressive suppression in those with SUDs relative to controls (Hedges' g = 0.76, 95% CI = 0.25-1.28, P = 0.004). CONCLUSIONS: People with substance use disorders appear to have greater difficulties in emotion regulation than people without substance use disorders.

Cannabis self-administration in the human laboratory: a scoping review of ad libitum studies.

Cannabis self-administration studies may be helpful for identifying factors that influence cannabis consumption and subjective response to cannabis. Additionally, these paradigms could be useful for testing novel pharmacotherapies for cannabis use disorder. This scoping review aims to summarize the findings from existing ad libitum cannabis self-administration studies to determine what has been learned from these studies as well as their limitations. We examined studies that specifically examined cannabis smoking, focusing on subjective response and self-administration behavior (e.g., smoking topography). A systematic search was conducted using PubMed and Embase from inception to October 22, 2022. Our search strategy identified 26 studies (total N = 662, 79% male) that met our eligibility criteria. We found that tetrahydrocannabinol (THC) concentration significantly affected subjective response to cannabis in some but not all studies. In general, cannabis self-administration tended to be most intense at the beginning of the laboratory session and decreased in later parts of the session. There was limited data on cannabis self-administration in adults older than 55. Data on external validity and test-retest reliability were also limited. Addressing these limitations in future ad libitum cannabis self-administration studies could lead to more valid and generalizable paradigms, which in turn could be used to improve our understanding of cannabis use patterns and to help guide medication development for cannabis use disorder.

Endocannabinoid System Biomarkers in Alzheimer's Disease.

Background: Alterations in the endocannabinoid system (ES) have been described in Alzheimer's disease (AD) pathophysiology. In the past years, multiple ES biomarkers have been developed, promising to advance our understanding of ES changes in AD. Discussion: ES biomarkers, including positron emission tomography with cannabinoid receptors tracers and biofluid-based endocannabinoids, are associated with AD disease progression and pathological features. Conclusion: Although not specific enough for AD diagnosis, ES biomarkers hold promise for prognosis, drug-target engagement, and a better understanding of the disease. Here, we summarize currently available ES biomarker findings and discuss their potential applications in the AD research field.

Repetitive transcranial magnetic stimulation for smoking cessation: Next steps for translation and implementation into clinical practice.

Tobacco smoking is a significant determinant of preventable morbidity and mortality worldwide. It is now possible to modulate the activity of the neurocircuitry associated with nicotine dependence using repetitive Transcranial Magnetic Stimulation (rTMS), a non-invasive neurostimulation approach, which has recently demonstrated efficacy in clinical trials and received regulatory approval in the US and Canada. However there remains a paucity of replication studies and real-world patient effectiveness data as access to this intervention is extremely limited. There are a number of unique challenges related to the delivery of rTMS that need to be addressed prior to widespread adoption and implementation of this treatment modality for smoking cessation. In this paper, we review the accessibility, scientific, technological, economical, and social challenges that remain before this treatment can be translated into clinical practice. By addressing these remaining barriers and scientific challenges with rTMS for smoking cessation and delineating implementation strategies, we can greatly reduce the burden of tobacco-related disease worldwide.

Treatment outcomes in major depressive disorder in patients with comorbid alcohol use disorder: A STAR*D analysis.

INTRODUCTION: Guidance on Major Depressive Disorder (MDD) treatment in those with comorbid Alcohol Use Disorder (AUD) is limited. We performed a secondary analysis on the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, examining the association between comorbid AUD and depression outcomes. METHODS: STAR*D was a real-world effectiveness trial starting with citalopram in level 1. Non-responding participants progressed through 3 other sequential treatment levels with different switch or augmentation options. Antidepressant outcomes were compared between MDD (n = 2826) and comorbid MDD and AUD (n = 864). Logistic regressions were performed to evaluate remission and response predictors in the total STAR*D sample and the AUD-comorbidity interaction. RESULTS: Chi-squared tests showed no significant difference in response or remission rates from depression between groups across treatment levels. Higher Hamilton Rating Scale for Depression (HRSD) score was associated with overall lower odds of remission in treatment level 1 (OR = 0.93, p < 0.001) and 2 (OR = 0.95, p < 0.001), with no significant interaction with comorbid AUD. Higher baseline suicidality had overall lower odds of remission in level 1 (OR = 0.82, p < 0.001) and 2 (OR = 0.1, p < 0.001), but with comorbid AUD compared to no AUD, suicidality increased odds of level 1 remission (OR = 1.30, p = 0.012). In comorbid AUD in level 2, venlafaxine was associated with lower odds of remission (OR = 0.13, p = 0.013) and response (OR = 0.12, p = 0.006); bupropion with lower odds of response (OR = 0.22, p = 0.024). LIMITATIONS: Open label study design and lack of alcohol use data. CONCLUSIONS: Comorbid AUD may interact with predictors of antidepressant response in MDD and using venlafaxine or bupropion may be less effective. Addressing this comorbidity requires unique assessment and treatment approaches.

Opioid receptor antagonism and neural response to monetary rewards: Pilot studies in light and heavy alcohol users.

Alcohol use disorder (AUD) is a prevalent condition associated with high degree of comorbidity and mortality. Among the few approved pharmacotherapies for AUD, two involve opioid receptor antagonism. Naltrexone and nalmefene are thought to act via opioid receptor blockage to reduce neural response to alcohol and drug-associated cues and consumption, but there have been limited efforts to characterize these effects in humans. In these studies, we sought to test the magnitude of opioid antagonism effects on neural response to monetary rewards in two groups: light drinkers (for the naltrexone study) and heavy drinkers (for the nalmefene study). We conducted double-blind, randomized, crossover pilot studies of reward activation in the brain following acute administration of opioid antagonist and placebo in 11 light and 9 heavy alcohol users. We used a monetary incentive delay task during functional MRI. We found a main effect of cue type on BOLD activation in the nucleus accumbens, demonstrating a neural reward response. The effect of opioid antagonism, relative to placebo, was small and nonsignificant for reward activation in the accumbens for both light and heavy alcohol users. Based on the results of two pilot studies, opioid antagonist medications do not appear to decrease neural activation to monetary rewards in the nucleus accumbens relative to placebo.

GABAergic signaling in alcohol use disorder and withdrawal: pathological involvement and therapeutic potential.

Alcohol is one of the most widely used substances. Alcohol use accounts for 5.1% of the global disease burden, contributes substantially to societal and economic costs, and leads to approximately 3 million global deaths yearly. Alcohol use disorder (AUD) includes various drinking behavior patterns that lead to short-term or long-lasting effects on health. Ethanol, the main psychoactive molecule acting in alcoholic beverages, directly impacts the GABAergic system, contributing to GABAergic dysregulations that vary depending on the intensity and duration of alcohol consumption. A small number of interventions have been developed that target the GABAergic system, but there are promising future therapeutic avenues to explore. This review provides an overview of the impact of alcohol on the GABAergic system, the current interventions available for AUD that target the GABAergic system, and the novel interventions being explored that in the future could be included among first-line therapies for the treatment of AUD.

Modeling ability to resist alcohol in the human laboratory: A pilot study.

Background: Roughly half of patients with alcohol use disorder prefer non-abstinence based approaches to treatment. However, only individuals who can limit their alcohol use after low-risk consumption are most likely to benefit from these approaches. This pilot study developed a laboratory-based intravenous alcohol self-administration paradigm to determine the characteristics of individuals who could successfully resist consuming alcohol after an initial exposure. Methods: Seventeen non-treatment seeking heavy drinkers completed two versions of an intravenous alcohol self-administration paradigm designed to assess impaired control over alcohol use. In the paradigm, participants received a priming dose of alcohol and then entered a 120-min resist phase, in which they received monetary rewards if they resisted self-administering alcohol. We used Cox proportional hazards regression to determine the impact of craving and Impaired Control Scale scores on rate of lapse. Results: 64.7% of participants across both versions of the paradigm were unable to resist alcohol for the duration of the session. Craving at baseline (HR = 1.07, 95% CI 1.01-1.13, p = 0.02) and following priming (HR = 1.08, 95% CI 1.02-1.15, p = 0.01) were associated with rate of lapse. Individuals who lapsed endorsed greater attempts to control their drinking over the prior six months compared to individuals who resisted. Conclusions: This study provides preliminary evidence that craving may be predictive of risk of lapse in individuals who are trying to limit alcohol intake after consuming a small initial amount of alcohol. Future studies should test this paradigm in a larger and more diverse sample.