Daily and Momentary Associations Between Gender Minority Stress and Resilience With Alcohol Outcomes.

BACKGROUND AND PURPOSE: Minority stressors have been linked with alcohol use among transgender and gender diverse (TGD); however, no ecological momentary assessment studies have examined daily links between minority stress and alcohol use specifically among TGD. This study examined gender minority stressors and resilience as predictors of same-day or momentary alcohol-related outcomes. Feasibility and acceptability of procedures were evaluated. METHODS: Twenty-five TGD adults (mean age = 32.60, SD = 10.82; 88% White) were recruited Canada-wide and participated remotely. They completed 21 days of ecological momentary assessment with daily morning and random surveys (assessing alcohol outcomes, risk processes, gender minority stressors, resilience), and an exit interview eliciting feedback. RESULTS: Gender minority stress had significant and positive within-person relationships with same-day alcohol use (incidence risk ratio (IRR) = 1.12, 95% confidence interval [CI] [1.02, 1.23]), alcohol-related harms (IRR = 1.14, 95% CI [1.02, 1.28]), and coping motives (IRR = 1.06, 95% CI [1.03, 1.08]), as well as momentary (past 30-min) alcohol craving (IRR = 1.32, 95% CI [1.18, 1.47]), coping motives (IRR = 1.35, 95% CI [1.21, 1.51]), and negative affect (IRR = 1.28, 95% CI [1.20, 1.36]). Gender minority stress indirectly predicted same-day drinking via coping motives (ab = 0.04, 95% CI [0.02, 0.08]). Resilience was positively associated with same-day alcohol use (IRR = 1.25, 95% CI [1.03, 1.51]) but not harms. CONCLUSIONS: TGD adults may use alcohol to cope with gender minority stress, which can increase the risk for alcohol-related harms. Interventions are needed to eliminate gender minority stressors and support adaptive coping strategies.

Many transgender and gender diverse (TGD) adults experience discrimination and victimization related to their minoritized gender, referred to as minority stress. Minority stress may put TGD adults at risk of drinking more alcohol and experiencing related harms in order to cope. To examine this possibility, we recruited 25 TGD adults and asked them to complete surveys multiple times per day (i.e., once daily in the morning, and two additional surveys at random times) on their personal cell phones. Using multilevel models, we examined the relations between experiencing minority stressors as well as resilience factors on alcohol-related outcomes. In doing so, we identified that gender minority stress was related to increased alcohol use, alcohol-related harms, negative mood, and drinking to cope motives. Furthermore, it appeared that the increased alcohol use following minority stress could be partly explained by desiring to drink to cope. Resilience did not protect TGD adults from increased alcohol use or harms, and in some cases was related to increased alcohol use. The results support that TGD adults may use alcohol to cope with gender minority stress, which can increase the risk for alcohol-related harms. Interventions are needed to eliminate gender minority stressors and support healthier coping strategies.

Interactive effects of alcohol and cannabis quantities in the prediction of same-day negative consequences among young adults.

BACKGROUND: Simultaneous alcohol and cannabis use is common, but observational studies examining negative consequences of simultaneous use have rarely considered dose-related interactions between alcohol and cannabis. This study examined interactions between quantities of cannabis and alcohol consumed in predicting negative consequences on simultaneous use days. METHODS: Young adults (N = 151; 64% female; 62% White) reporting recent simultaneous use and at least weekly alcohol and cannabis use completed 21 daily, smartphone-based surveys assessing previous day quantities of cannabis and alcohol used, types of cannabis used (flower, concentrates, edibles), and negative substance-related consequences. Multilevel models examined: (1) whether negative consequences differed within-person across simultaneous use days and single-substance use days; and (2) whether quantities of alcohol and cannabis consumed on simultaneous use days interacted, within-person, to predict negative consequences. We focused on quantities of cannabis flower (grams) in primary analyses and explored quantities of other forms of cannabis (concentrates, edibles) in supplementary analyses. RESULTS: Participants reported fewer negative consequences on alcohol-only (243 observations) and cannabis-only (713 observations) days than they did on simultaneous use days (429 observations). On simultaneous use days involving cannabis flower use (313 observations across 81 participants), the within-person association between number of standard drinks and negative consequences was weaker on days during which larger (vs. smaller) amounts of cannabis flower were consumed. Inspection of simple slopes revealed that decreased alcohol use was associated with less of a decline in negative consequences when combined with relatively greater amounts of cannabis flower. CONCLUSIONS: Although simultaneous use was associated with more negative consequences than alcohol-only and cannabis-only use, negative consequences on simultaneous use days varied as a function of the interaction between alcohol and cannabis quantities. As findings suggest that using larger amounts of cannabis may attenuate declines in negative consequences associated with lighter drinking, interventions for higher-risk simultaneous use patterns may benefit from a focus on quantities of both alcohol and cannabis.

Perceptions, Experiences, and Patterns of Cannabis Use in Individuals with Mood and Anxiety Disorders in the Context of Cannabis Legalization and Medical Cannabis Program in Canada - A Qualitative Study.

INTRODUCTION: Perceptions of cannabis as a potential medical treatment for mood and anxiety disorders have been increasing in the context of legalizations, availability, and medical cannabis programs, though current evidence predominately indicates risks and negative effects of cannabis use (CU) on mental health outcomes. This study aims to understand motivations, perceptions, effects, and patterns of CU in individuals with mood and anxiety disorders. METHODS: Thirty-six adult patients diagnosed with mood or anxiety disorders, obsessive-compulsive disorder, or posttraumatic stress disorder who were currently using cannabis completed an in-depth qualitative interview on individual motivations, perceptions, experiences, effects, and patterns of their CU. The thematic analysis focused on phases of CU and sources of cannabis products and information. RESULTS: Reported motivations for initiation of CU included curiosity, peer pressure, and dissatisfaction with conventional treatments. Factors such as psychotropic effects and coping with mental health symptoms and insomnia contributed to the continuation of CU. More negative effects, including cognitive dysfunction, worsening of mood, and anxiety symptoms, were acknowledged with ongoing CU. Concerning findings included common initiation of CU before age 18, combined medical and recreational CU, rare consultation of medical professionals on CU, and potential effects and harms. DISCUSSION: Findings indicate individual complexity of motivations, perceptions, and patterns of CU in the study population. The reported potential beneficial effects of specific cannabis products should be further investigated. Findings emphasize patient-provider dialogue on both CU and conventional treatments. Information from this study can contribute to and inform the development of education, prevention, and intervention strategies.

How much THC is in that joint? A daily diary study of young adults' knowledge of the cannabinoid content of cannabis products.

OBJECTIVE: Many young adults report frequent cannabis use and are at risk for cannabis harms. Knowledge of the tetrahydrocannabinol (THC) and cannabidiol (CBD) concentrations of cannabis products may promote harm reduction, but few studies have characterized cannabinoid concentration knowledge in this population. This study used day-level data to examine predictors of cannabinoid concentration knowledge and associations of cannabinoid concentration knowledge with substance-related consequences among young adults. METHOD: Participants (N=131; mean age 22.11 years, 64.12% female) from a larger study of cannabis and alcohol co-use completed daily surveys over 21 days assessing knowledge of the cannabinoid concentrations of cannabis used, forms of cannabis used, motives for cannabis use (medicinal, nonmedicinal, both), and substance-related consequences. RESULTS: On average, participants reported at least some knowledge of the THC and CBD concentrations of their cannabis on a respective 48% and 32% of their cannabis days. Generalized linear mixed models revealed that participants with a greater propensity to use non-flower (relative to flower) cannabis products and to report medicinal (relative to exclusively non-medicinal) motives for cannabis use reported greater cannabinoid concentration knowledge overall across days, controlling for sociodemographic factors and level of cannabis involvement. Participants with greater overall cannabinoid concentration knowledge reported positive substance-related consequences more often. In addition, participants were more likely to report negative substance-related consequences on days during which cannabinoid concentrations were known versus unknown. CONCLUSIONS: Findings suggest that cannabinoid concentration knowledge may be higher among young adults who report primarily non-flower and medicinally-motivated cannabis use, although cannabinoid concentration knowledge, alone, may not protect against negative substance-related consequences at the day level.

Effects of Nicotine Content and Preferred Flavor on Subjective Responses to E-cigarettes: A Randomized, Placebo-controlled Laboratory Study.

INTRODUCTION: Evidence suggests that e-liquid flavor and nicotine concentration are important factors in the initiation and maintenance of e-cigarette use (vaping). Flavors may increase the initiation and maintenance of vaping, and nicotine content is a factor in e-cigarette dependence and the efficacy of e-cigarettes for cigarette smoking cessation. Few human laboratory studies have assessed the joint and interactive effects of flavor and nicotine on subjective responses to e-cigarettes. METHODS: Regular e-cigarette users (N = 89) completed a multi-session study involving a paced vaping procedure with e-liquid cartridges containing their preferred flavor (berry, menthol, or tobacco) or no flavor, with or without nicotine (18 mg). Subjective effects of vaping (satisfaction, reward, aversion, airway sensations, and craving relief) were assessed. RESULTS: Nicotine significantly increased psychological reward and craving relief, whereas flavor significantly increased vaping satisfaction and taste. Nicotine dependence severity moderated the effect of nicotine on reward, such that those with the greatest dependence severity reported the greatest reward. CONCLUSIONS: These findings support differential and noninteractive effects of e-liquid nicotine content and flavor on reinforcing effects of e-cigarettes. IMPLICATIONS: E-liquid flavor and nicotine content have independent, non-interactive effects on subjective responses to vaping under controlled laboratory conditions. Among regular e-cigarette users, vaping a preferred flavor increased taste and satisfaction, but did not interact with nicotine to alter reward or craving. Further research on the ways in which these subjective effects may motivate vaping behavior among different populations of e-cigarette users would be useful to inform regulatory policy of ENDS products.

Social Media as Pharmacovigilance: The Potential for Patient Reports to Inform Clinical Research on Glucagon-Like Peptide 1 (GLP-1) Receptor Agonists for Substance Use Disorders.

The surge in popularity of semaglutide (Ozempic, Wegovy, Rybelsus) and other glucagon-like-peptide 1 (GLP-1) receptor agonists has been accompanied by widespread reports of unintended reductions in alcohol use (and other addictive behaviors) during treatment. With clinical trials of GLP-1 receptor agonists for substance use only recently under way, anecdotal reports (including via social media) are now a primary reason for interest in potential effects of GLP-1 receptor agonists on alcohol use in patient populations. The nature and volume of these reports raises the prospect that social media data can potentially be leveraged to inform the study of novel addiction treatments and the prioritization of behavioral or neurobiological targets for mechanistic research. This approach, which aligns with recent efforts to apply social media data to pharmacovigilance, may be particularly relevant for drug repurposing efforts. This possibility is illustrated by a thematic analysis of anonymous online reports concerning changes in alcohol use or alcohol-related effects during treatment with GLP-1 receptor agonists. These reports not only support the rationale for clinical trials but also point to potential neurobehavioral mechanisms (e.g., satiety, craving/preoccupation, aversion, altered subjective response) that might inform hypotheses for human laboratory and neuroscience studies. Refined methods for capturing patient reports of incidental medication effects on addictive behaviors at large scale could potentially lead to novel, pharmacovigilance-based approaches to identify candidate therapies for drug repurposing efforts.

Knowledge of Cannabinoid Content Among People Living with HIV Who Use Cannabis: a Daily Diary Study.

BACKGROUND: Many people living with HIV (PLWH) use cannabis for medicinal reasons. Patients' knowledge of the tetrahydrocannabinol (THC) and cannabidiol (CBD) concentrations of the cannabis products they use may be important in helping patients achieve symptom relief while guarding against potential risks of cannabis use. However, no studies have examined cannabinoid concentration knowledge among PLWH. METHOD: PLWH (N = 29; 76% men, mean age 47 years) reporting cannabis use for both medicinal and nonmedicinal reasons completed daily surveys over 14 days assessing cannabis products used, knowledge of cannabinoid concentrations of cannabis products used, cannabis use motives (medicinal, nonmedicinal, both), and positive and negative cannabis-related consequences. Across the 361 cannabis use days captured on the daily surveys, at least some knowledge of cannabinoid concentrations was reported on an average of 43.1% (for THC) and 26.6% (for CBD) of the days. RESULTS: Generalized linear mixed models revealed that participants were more likely to report knowing THC and CBD concentrations on days when they used non-flower forms of cannabis relative to days when they used cannabis flower only. Participants who used cannabis for medicinal reasons on a greater proportion of days had greater knowledge of cannabinoid concentration overall across days. Further, greater overall knowledge of cannabinoid concentrations was associated with fewer reported negative cannabis-related consequences. CONCLUSIONS: Findings suggest that among PLWH, knowledge of cannabinoid concentrations may be higher when using non-flower cannabis products and among those reporting primarily medicinal cannabis use. Moreover, knowledge of cannabinoid concentration may protect against negative cannabis-related consequences in this population.

Executive functions and behavioral economic demand for cannabis among young adults: Indirect associations with cannabis consumption and cannabis use disorder.

Behavioral economic demand for cannabis is robustly associated with cannabis consumption and cannabis use disorder (CUD). However, few studies have examined the processes underlying individual differences in the relative valuation of cannabis (i.e., demand). This study examined associations between executive functions and cannabis demand among young adults who use cannabis. We also examined indirect associations of executive functions with cannabis consumption and CUD symptoms through cannabis demand. Young adults (N = 113; 58.4% female; mean age 22 years) completed a Marijuana Purchase Task. Participants also completed cognitive tasks assessing executive functions (set shifting, inhibitory control, working memory) and semistructured interviews assessing past 90-day cannabis consumption (number of grams used) and number of CUD symptoms. Poorer inhibitory control was significantly associated with greater Omax (peak expenditure on cannabis) and greater intensity (cannabis consumption at zero cost). Poorer working memory was significantly associated with lower elasticity (sensitivity of consumption to escalating cost). Lower inhibitory control was indirectly associated with greater cannabis consumption and CUD symptoms through greater Omax and intensity, and poorer working memory was indirectly associated with greater cannabis consumption and CUD symptoms through reduced elasticity. This study provides novel evidence that executive functions are associated with individual differences in cannabis demand. Moreover, these results suggest that cannabis demand could be a mechanism linking poorer executive functioning with heavier cannabis use and CUD, which should be confirmed in future longitudinal studies. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Meta-analysis of acute alcohol effects on response inhibition.

Alcohol intoxication impairs response inhibition; however, discrepant findings have been reported regarding the magnitude and moderators of this effect. This meta-analysis of human laboratory studies aimed to quantify acute effects of alcohol on response inhibition and evaluate moderators of this effect. Eligible studies examined alcohol's effects on response inhibition with the Go/No-Go (GNG) task (n = 1616 participants) or Stop Signal Task (SST) (n = 1310 participants). Results revealed a detrimental effect of acute alcohol on response inhibition overall (g = 0.411, 95 % CI [0.350, 0.471]), with similar effects in studies using GNG (g = 0.431, SE = 0.031) and SST (g = 0.366, SE = 0.063). Effect sizes were larger in studies involving higher breath alcohol concentration levels and under GNG conditions that established a prepotent response set. These findings establish the magnitude, precision, and potential moderators of alcohol's effects on inhibitory control, furthering understanding of a key neurobehavioral mechanism proposed to underlie alcohol-related impulsivity and impaired control over consumption.

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.

Daily associations between cannabis use and alcohol use among people who use cannabis for both medicinal and nonmedicinal reasons: Substitution or complementarity?

OBJECTIVE: People who use cannabis for medicinal (vs. nonmedicinal) reasons report greater cannabis use and lower alcohol use, which may reflect a cannabis-alcohol substitution effect in this population. However, it is unclear whether cannabis is used as a substitute or complement to alcohol at the day level among people who use cannabis for both medicinal and nonmedicinal reasons. This study used ecological momentary assessment to examine this question. METHOD: Participants (N = 66; 53.1% men; mean age 33 years) completed daily surveys assessing previous-day reasons for cannabis use (medicinal vs. nonmedicinal), cannabis consumption (both number of different types of cannabis used and grams of cannabis flower used), and number of standard drinks consumed. RESULTS: Multilevel models revealed that, in general, greater cannabis consumption on a given day was associated with greater same-day alcohol use. Further, days during which cannabis was used for medicinal (vs. exclusively nonmedicinal) reasons were associated with reduced consumption of both cannabis and alcohol. The day-level association between medicinal reasons for cannabis use and lower alcohol consumption was mediated by using fewer grams of cannabis on medicinal cannabis use days. CONCLUSIONS: Day-level cannabis-alcohol associations may be complementary rather than substitutive among people who use cannabis for both medicinal and nonmedicinal reasons, and lower (rather than greater) cannabis consumption on medicinal use days may explain the link between medicinal reasons for cannabis use and reduced alcohol use. Still, these individuals may use greater amounts of both cannabis and alcohol when using cannabis for exclusively nonmedicinal reasons. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Association Between Fatty Acid Amide Hydrolase and Alcohol Response Phenotypes: A Positron Emission Tomography Imaging Study With [11C]CURB in Heavy-Drinking Youth.

BACKGROUND: Reductions in fatty acid amide hydrolase (FAAH), the catabolic enzyme for the endocannabinoid anandamide, may play a role in drinking behavior and risk for alcohol use disorder. We tested the hypotheses that lower brain FAAH levels in heavy-drinking youth are related to increased alcohol intake, hazardous drinking, and differential response to alcohol. METHODS: FAAH levels in the striatum, prefrontal cortex, and whole brain were determined using positron emission tomography imaging of [11C]CURB in heavy-drinking youth (N = 31; 19-25 years of age). C385A FAAH genotype (rs324420) was determined. Behavioral (n = 29) and cardiovascular (n = 22) responses to alcohol were measured during a controlled intravenous alcohol infusion. RESULTS: Lower [11C]CURB binding was not significantly related to frequency of use but was positively associated with hazardous drinking and reduced sensitivity to the negative effects of alcohol. During alcohol infusion, lower [11C]CURB binding related to greater self-reported stimulation and urges and lower sedation (p < .05). Lower heart rate variability was related to both greater alcohol-induced stimulation and lower [11C]CURB binding (p < .05). Family history of alcohol use disorder (n = 14) did not relate to [11C]CURB binding. CONCLUSIONS: In line with preclinical studies, lower FAAH in the brain was related to a dampened response to the negative, impairing effects of alcohol, increased drinking urges, and alcohol-induced arousal. Lower FAAH might alter positive or negative effects of alcohol and increase urges to drink, thereby contributing to the addiction process. Determining whether FAAH influences motivation to drink through increased positive/arousing effects of alcohol or greater tolerance should be investigated.

Explanatory pathways linking anxiety sensitivity and alcohol (mis)use: A prospective state-trait analysis among emerging adults.

OBJECTIVE: Alcohol use and related problems increase during adolescence and peak in early adulthood. Tension reduction theories suggest that those high in anxiety sensitivity (AS) may be at risk for misusing alcohol for its anxiolytic effects. Cognitive theories point to drinking motives and alcohol expectancies as explanatory mechanisms of this risk pathway. This study examined AS risk for prospective alcohol misuse, as explained by an unfolding cognitive process, among those transitioning out of Collège d'enseignement général et professionnel (CEGEP, i.e., junior college equivalent in Quebec, Canada). We hypothesized that there would be trait-like (average levels over time), positive associations between AS, coping motives, tension-reduction alcohol expectancies, and alcohol use and problems, and that AS would lead to state-like (occasion-specific, reciprocal associations) bidirectional and positive associations between alcohol cognitions and outcomes. METHOD: Final-year CEGEP students (N = 193) completed three online questionnaires at 6-month intervals assessing AS, drinking motives (coping, enhancement), alcohol expectancies (tension reduction, sociability/liquid courage), and alcohol use/problems. State-trait modeling was used for hypothesis testing. RESULTS: Consistent with hypotheses, at the "trait" level, drinking motives and alcohol expectancies were positively associated, and drinking motives and sociability/liquid courage expectancies were positively associated with alcohol problems. At the "state" level, AS positively predicted coping motives and alcohol use, tension-reduction expectancies positively predicted coping motives, and coping motives and sociability/liquid courage expectancies positively predicted alcohol use. CONCLUSIONS: Results suggest that AS is a risk factor for coping-motivated drinking, and that there is interplay between cognitions that may help understand emerging adult alcohol risk pathways. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Disentangling Medicinal and Recreational cannabis Use Among People Living with HIV: An Ecological Momentary Assessment Study.

This study examined the feasibility of using ecological momentary assessment (EMA) to disentangle medicinal cannabis use (MCU) from recreational cannabis use (RCU) among people living HIV (PLWH). Over a 14-day period, PLWH (N = 29) who engaged in both MCU and RCU completed a smartphone-based survey before and after every cannabis use event assessing general motivation for cannabis use (MCU-only, RCU-only, or mixed MCU/RCU), cannabis use behavior, and several antecedents and outcomes of cannabis use. A total of 739 pre-cannabis surveys were completed; 590 (80%) of the prompted post-cannabis surveys were completed. Motives for cannabis use were reported as MCU-only on 24%, RCU-only on 30%, and mixed MCU/RCU on 46% of pre-cannabis surveys. Mixed effects models examined within-person differences across MCU-only, RCU-only, and mixed MCU/RCU events. Results showed that relative to RCU-only events, MCU-only events were more likely to involve symptom management and drug substitution motives, physical and sleep-related symptoms, solitary cannabis use, and use of cannabis oils and sprays; MCU-only events were less likely to involve relaxation, happiness, and wellness motives, cannabis flower use, and positive cannabis consequences. Differences between mixed MCU/RCU and RCU-only events were similar, except that mixed MCU/RCU events were additionally associated with stress reduction motives and symptoms of anxiety and depression. Findings support the feasibility of partially disentangling MCU and RCU behavior among PLWH who engage in concurrent MCU and RCU. This study highlights the need for more EMA studies isolating MCU from RCU to inform ongoing changes to cannabis policies.

Effects of varenicline and bupropion on laboratory smoking outcomes: Meta-analysis of randomized, placebo-controlled human laboratory studies.

Human laboratory studies are widely used to evaluate behavioural mechanisms of pharmacotherapy effects. Results from human laboratory studies examining smoking cessation pharmacotherapies have not been examined in aggregate. The current meta-analysis aimed to synthesize data from randomized, placebo-controlled human laboratory studies on the effects of non-nicotine pharmacotherapies on outcomes relevant for smoking cessation. Literature searches identified 15 human laboratory studies of varenicline (n = 697) and 9 studies of bupropion (n = 313) with sufficient data for inclusion. Studies involved acute or subacute pharmacotherapy treatment with administration durations ranging from a single dose to 8 weeks. Primary outcomes examined were craving, withdrawal and behavioural indices of smoking. Varenicline significantly reduced craving (Hedge's g = -0.36[-0.54,-0.17], p < 0.001), withdrawal (g = -0.25[-0.41,-0.09], p = 0.003) and behavioural indices of smoking (g = -0.36[-0.63,-0.08], p = 0.01) relative to placebo. In contrast, results were inconclusive regarding bupropion's effects on craving (g = -0.13[-0.32,0.05], p = 0.15), withdrawal (g = -0.15[-0.44,0.14], p = 0.31) and behavioural indices of smoking (g = -0.05[-0.35,0.24], p = 0.73) relative to placebo. Findings provide meta-analytic support that short-term varenicline treatment decreases craving, withdrawal symptoms and smoking behaviour under controlled laboratory conditions. However, findings also suggest the ability of human laboratory paradigms to detect pharmacotherapy effects may differ by treatment type. Pharmacotherapy discovery and evaluation efforts utilizing human laboratory methods should aim to align study designs and laboratory procedures with presumed therapeutic mechanisms when possible.

Therapeutic Potential of Histamine H3 Receptors in Substance Use Disorders.

Substance use disorders are a leading cause of morbidity and mortality, and available pharmacological treatments are of modest efficacy. Histamine is a biogenic amine with four types of receptors. The histamine H3 receptor (H3R) is an autoreceptor and also an heteroreceptor. H3Rs are highly expressed in the basal ganglia, hippocampus and cortex, and regulate a number of neurotransmitters including acetylcholine, norepinephrine, GABA and dopamine. Its function and localization suggest that the H3R may be relevant to a number of psychiatric disorders and could represent a potential therapeutic target for substance use disorders. The purpose of the present review is to summarize preclinical studies investigating the effects of H3R agonists and antagonists on animal models of alcohol, nicotine and psychostimulant use. At present, the effects of H3R antagonists such as thioperamide, pitolisant or ciproxifan have been investigated in drug-induced locomotion, conditioned place preference, drug self-administration, reinstatement, sensitization and drug discrimination. For alcohol and nicotine, the effects of H3R ligands on two-bottle choice and memory tasks, respectively, have also been investigated. The results of these studies are inconsistent. For alcohol, H3R antagonists generally decreased the reward-related properties of ethanol, which suggests that H3R antagonists may be effective as a treatment option for alcohol use disorder. However, the effects of H3R antagonists on nicotine and psychostimulant motivation and reward are less clear. H3R antagonists potentiated the abuse-related properties of nicotine, but only a handful of studies have been conducted. For psychostimulants, evidence is mixed and suggests that more research is needed to establish whether H3R antagonists are a viable therapeutic option. The fact that different drugs of abuse have different brain targets may explain the differential effects of H3R ligands.

Randomized controlled trial of online interventions for co-occurring depression and hazardous alcohol consumption: Primary outcome results.

BACKGROUND AND AIMS: The current trial tested the benefits of offering a brief online intervention for hazardous alcohol consumption along with one for depression among people experiencing both conditions. METHODS: Online advertisements were used to recruit people with persistent low mood. Those who also had current hazardous alcohol consumption were identified and invited to take part in the trial (those not eligible were offered access to the online depression intervention). Participants were randomized to an established intervention for depression (MoodGYM; M-only) or to receive MoodGYM plus a brief personalized feedback intervention for hazardous drinking (Check Your Drinking; M + CYD). Participants were followed-up at three and six months. RESULTS: While levels of depression symptoms (p < .001) and hazardous alcohol consumption (p < .001) reduced in both the M-only and the M + CYD groups, there was no difference between groups on drinking (p = .374) or depression outcomes (p = .752). Further, participants who were provided both interventions logged into the intervention website less often (M = 4.1, SD = 3.9) compared to participants only offered the depression intervention (M = 4.9, SD = 5.2), t (986) = 2.47, p = .014. However, there was no significant difference (p > .05) in the number of MoodGYM modules completed between the two groups. DISCUSSION AND CONCLUSION: The current trial found no benefit to providing a brief online intervention for hazardous alcohol consumption alongside one for depression among people experiencing these co-occurring disorders. Further, the finding that adding an online intervention for drinking to one for depression led to a small reduction in the number of times the interventions were accessed implies the need for caution when deciding how best to provide online help to those with co-occurring depression and hazardous alcohol consumption.Trial Registration: ClinicalTrials.govNCT03421080.

Exploring regulation and function of dopamine D3 receptors in alcohol use disorder. A PET [11C]-(+)-PHNO study.

Preclinical studies support an important role of dopamine D3 receptors (DRD3s) in alcohol use disorder (AUD). In animals, voluntary alcohol consumption increases DRD3 expression, and pharmacological blockade of DRD3s attenuates alcohol self-administration and reinstatement of alcohol seeking. However, these findings have yet to be translated in humans. This study used positron emission tomography (PET) and [11C]-(+)-PHNO to compare receptor levels in several dopamine D2 receptor (DRD2) and DRD3 regions of interest between AUD subjects in early abstinence (n = 17; 6.59 ± 4.14 days of abstinence) and healthy controls (n = 18). We recruited non-treatment seeking subjects meeting DSM-5 criteria for AUD. We examined the relationship between DRD2/3 levels and both alcohol craving and alcohol motivation/wanting, using a cue reactivity procedure and an intravenous alcohol self-administration (IVASA) paradigm, respectively. [11C]-(+)-PHNO binding levels in AUD subjects were significantly lower than binding in HCs when looking at all DRD2/3 ROIs jointly (Wilk's Λ = .58, F(6,28) =3.33, p = 0.013, η2p = 0.42), however there were no region-specific differences. Binding values demonstrate -12.3% and -16.1% lower [11C]-(+)-PHNO binding in the SMST and SN respectively, though these differences did not withstand Bonferroni corrections. There was a positive association between [11C]-(+)-PHNO binding in the SN (almost exclusively reflective of DRD3) and alpha (lower values reflect higher alcohol demand) in the APT after Bonferroni corrections (r = 0.66, p = 0.0080). This demonstrates that AUD subjects with lower DRD3 levels in the SN exhibit increased demand for alcohol. These results replicate previous findings demonstrating reduced DRD2/3 levels while also supporting a lack of DRD3 upregulation and potential downregulation in early abstinent AUD. Furthermore, the finding that binding in the SN is associated with alcohol demand warrants further examination.

Machine learning prediction of blood alcohol concentration: a digital signature of smart-breathalyzer behavior.

Excess alcohol use is an important determinant of death and disability. Machine learning (ML)-driven interventions leveraging smart-breathalyzer data may help reduce these harms. We developed a digital phenotype of long-term smart-breathalyzer behavior to predict individuals' breath alcohol concentration (BrAC) levels trained on data from a smart breathalyzer. We analyzed roughly one million datapoints from 33,452 users of a commercial smart-breathalyzer device, collected between 2013 and 2017. For validation, we analyzed the associations between state-level observed smart-breathalyzer BrAC levels and impaired-driving motor vehicle death rates. Behavioral, geolocation-based, and time-series-derived features were fed to an ML algorithm using training (70% of the cohort), development (10% of the cohort), and test (20% of the cohort) sets to predict the likelihood of a BrAC exceeding the legal driving limit (0.08 g/dL). States with higher average BrAC levels had significantly higher alcohol-related driving death rates, adjusted for the number of users per state B (SE) = 91.38 (15.16), p < 0.01. In the independent test set, the ML algorithm predicted the likelihood of a given user-initiated BrAC sample exceeding BrAC ≥ 0.08 g/dL, with an area under the curve (AUC) of 85%. Highly predictive features included users' prior BrAC trends, subjective estimation of their BrAC (or AUC = 82% without the self-estimate), engagement and self-monitoring, time since the last measure, and hour of the day. In conclusion, an ML algorithm successfully quantified a digital phenotype of behavior, predicting naturalistic BrAC levels exceeding 0.08 g/dL (a threshold associated with alcohol-related harm) with good discrimination capability. This result establishes a foundation for future research on precision behavioral medicine digital health interventions using smart breathalyzers and passive monitoring approaches.