Attentional Bias, Pupillometry, and Spontaneous Blink Rate: Eye Characteristic Assessment Within a Translatable Nicotine Cue Virtual Reality Paradigm.

Background: Incentive salience processes are important for the development and maintenance of addiction. Eye characteristics such as gaze fixation time, pupil diameter, and spontaneous eyeblink rate (EBR) are theorized to reflect incentive salience and may serve as useful biomarkers. However, conventional cue exposure paradigms have limitations that may impede accurate assessment of these markers. Objective: This study sought to evaluate the validity of these eye-tracking metrics as indicators of incentive salience within a virtual reality (VR) environment replicating real-world situations of nicotine and tobacco product (NTP) use. Methods: NTP users from the community were recruited and grouped by NTP use patterns: nondaily (n=33) and daily (n=75) use. Participants underwent the NTP cue VR paradigm and completed measures of nicotine craving, NTP use history, and VR-related assessments. Eye-gaze fixation time (attentional bias) and pupillometry in response to NTP versus control cues and EBR during the active and neutral VR scenes were recorded and analyzed using ANOVA and analysis of covariance models. Results: Greater subjective craving, as measured by the Tobacco Craving Questionnaire-Short Form, following active versus neutral scenes was observed (F1,106=47.95; P<.001). Greater mean eye-gaze fixation time (F1,106=48.34; P<.001) and pupil diameter (F1,102=5.99; P=.02) in response to NTP versus control cues were also detected. Evidence of NTP use group effects was observed in fixation time and pupillometry analyses, as well as correlations between these metrics, NTP use history, and nicotine craving. No significant associations were observed with EBR. Conclusions: This study provides additional evidence for attentional bias, as measured via eye-gaze fixation time, and pupillometry as useful biomarkers of incentive salience, and partially supports theories suggesting that incentive salience diminishes as nicotine dependence severity increases.

Virtual Reality Environmental Enrichment Effects on Craving for Cigarette in Smokers.

Background: Preclinical studies suggested the exposure to environmental enrichment (EE) as an intervention able to prevent or reduce nicotine-taking and nicotine-seeking behaviors. Virtual reality (VR) may help to test the effects of EE in smokers in a reproducible and feasible manner. Materials and Methods: In the present study, 31 smokers (14 women) were divided into two groups: (1) exposure to a virtual EE (VR-EE) and (2) exposure to a virtual neutral environment (VR-NoEE). Cigarette craving was assessed as basal and evoked, at different timepoints during the session. Behavior activity during VR exposure, mood, and subjective measures were also collected. Results: EE exposure in VR significantly reduced craving scores from basal timepoint. This was not observed in the VR-NoEE group, which significantly increased craving compared with values at neutral scenario. When both groups were exposed to smoking-related VR scenario, the VR-EE group showed an increased craving compared with previous timepoint up to score values not different from those in the VR-NoEE group. A significant positive correlation between basal craving scores and interactive behavior with virtual smoking cues was observed in the VR-NoEE but not in the VR-EE group. Conclusion: These findings suggest that virtual EE might have an inhibitory effect in smokers on basal, but not on evoked cigarette craving. Noteworthily, the interactive activity correlation to craving scores in the VR-NoEE participants was not observed in the VR-EE group, adding further evidence that the enrichment simulation was nonetheless able to modify behavior in the smoking-related scenario.

Effect of N-acetylcysteine on neural alcohol cue reactivity and craving in adolescents who drink heavily: A preliminary randomized clinical trial.

BACKGROUND: Alcohol craving is related to problematic alcohol use; therefore, pharmacotherapies that modulate alcohol craving are of interest. N-acetylcysteine, an over-the-counter antioxidant, is a candidate pharmacotherapy for adolescent alcohol use with the potential to impact craving. Cue-reactivity paradigms using functional magnetic resonance imaging (fMRI) can identify neural regions implicated in craving and serve as a screening tool for novel pharmacotherapy options. METHODS: This preliminary study examined the effect of N-acetylcysteine on neural reactivity to alcohol cues and subjective craving among 31 non-treatment-seeking adolescents (17.6-19.9 years old, 55% female) who use alcohol heavily. In a randomized cross-over design, participants completed three fMRI sessions: baseline and after a 10-day course of N-acetylcysteine (1200 mg twice daily) and matched placebo. The primary outcome was neural response to alcohol versus non-alcohol beverage cues after N-acetylcysteine versus placebo, with a secondary outcome of self-reported subjective craving. RESULTS: In the full sample (n = 31), there was no effect of N-acetylcysteine versus placebo on neural alcohol reactivity (ps ≥ 0.49; η p 2 $$ {\upeta_{\mathrm{p}}}^2 $$ s = 0.00-0.07) or self-reported acute alcohol craving (p = 0.18, η p 2 $$ {\upeta_{\mathrm{p}}}^2 $$ = 0.06). However, N-acetylcysteine did reduce self-reported generalized alcohol craving (p = 0.03, η p 2 $$ {\upeta_{\mathrm{p}}}^2 $$ = 0.15). In a subsample of youth who met criteria for past-year alcohol use disorder (n = 19), results remained unchanged. CONCLUSIONS: N-acetylcysteine may not alter neural reactivity to alcohol cues or acute craving; however, it may reduce general subjective alcohol craving among adolescents who consume alcohol heavily.

Trajectories of craving in the course of pharmacotherapy trials for methamphetamine use disorder.

AIMS: The aim of this study was to measure trajectories of craving for methamphetamine during the course of pharmacotherapy trials for methamphetamine use disorder. DESIGN, SETTING AND PARTICIPANTS: Craving trajectories were identified using Group-Based Trajectory Modeling. The association of craving trajectories with drug use trajectories was examined using a dual trajectory model. Association of craving trajectories with other health and social outcomes was also examined. The study used pooled data from five randomized controlled pharmacotherapy trials for methamphetamine use disorder. A total of 866 adults with methamphetamine use disorder participated in randomized controlled pharmacotherapy trials. MEASUREMENT: Craving was assessed weekly using the Brief Substance Craving Scale. Drug use was assessed using urine toxicology. Alcohol- and drug-related problems, as well as psychiatric, medical, legal, employment and relationship problems, were measured using the Addiction Severity Index. FINDINGS: A three-trajectory model with high, medium and low craving trajectories was selected as the most parsimonious model. Craving trajectories were associated with methamphetamine use trajectories in the course of trial; 88.4% of those in the high craving trajectory group had a consistently high frequency of methamphetamine use compared with 18.7% of those in the low craving group. High craving was also associated with less improvement in most other outcomes and higher rate of dropout from treatment. In turn, low craving was associated with a rapidly decreasing frequency of methamphetamine use, greater improvement in most other outcomes and a lower rate of dropout. Participants on modafinil daily and ondansetron 1 mg twice daily were less likely to be in the high craving group compared with those on placebo. CONCLUSIONS: Trajectories of methamphetamine craving in the course of clinical trials for methamphetamine use disorder appear to be both highly variable and strongly associated with greater frequency of drug use, other drug-related outcomes and dropout from trials. Two medications, modafinil daily and ondansetron at a dose of 1 mg two times daily, appear to be associated with greater reduction in craving in the course of treatment compared with placebo. A decrease in methamphetamine craving shows promise as an early indicator of recovery from methamphetamine use disorder.

Multimodal frontal neuroimaging markers predict longitudinal craving reduction in abstinent individuals with heroin use disorder.

The variation in improvement among individuals with addiction after abstinence is a critical issue. Here, we aimed to identify robust multimodal markers associated with high response to 8-month abstinence in the individuals with heroin use disorder (HUD) and explore whether the identified markers could be generalized to the individuals with methamphetamine use disorder (MUD). According to the median of craving changes, 53 individuals with HUD with 8-month abstinence were divided into two groups: higher craving reduction and lower craving reduction. At baseline, clinical variables, cortical thickness and subcortical volume, fractional anisotropy (FA) of fibers and resting-state functional connectivity (RSFC) were extracted. Different strategies (single metric, multimodal neuroimaging fusion and multimodal neuroimaging-clinical data fusion) were used to identify reliable features for discriminating the individuals with HUD with higher craving reduction from those with lower reduction. The generalization ability of the identified features was validated in the 21 individuals with MUD. Multimodal neuroimaging-clinical fusion features with best performance was achieved an 87.1 ± 3.89% average accuracy in individuals with HUD, with a moderate accuracy of 66.7% when generalizing to individuals with MUD. The multimodal neuroimaging features, primarily converging in frontal regions (e.g., the left superior frontal (LSF) thickness, FA of the LSF-occipital tract, and RSFC of left middle frontal-right superior temporal lobe), collectively contributed to prediction alongside dosage and attention impulsiveness. In this study, we identified the validated multimodal frontal neuroimaging markers associated with higher response to long-term abstinence and revealed insights for the neural mechanisms of addiction abstinence, contributing to clinical strategies and treatment for addiction.

Transcranial Direct Current Stimulation for Food Craving in Women Affected by Overweight and Obesity: A Randomized Controlled Trial.

INTRODUCTION: Craving is a multifactorial behavior caused by central circuit imbalance. The proposed treatments involve exercise and reduced food intake. However, the treatments frequently fail. This study aimed to investigate the effect of 10 consecutive sessions of anodal transcranial direct current stimulation over the right dorsolateral prefrontal cortex on food craving and eating consumption of women affected by overweight and obesity. METHODS: A randomized double-blind controlled trial with 50 volunteers was divided into two groups (active-tDCS: n = 25 and sham-tDCS: n = 25). There were a total of 10 consecutive tDCS sessions (2 mA, for 20 min) with an F4 anodal-F3 cathodal montage. We evaluated the effects on eating behavior (food craving, uncontrolled eating, emotional eating, and cognitive restriction), food consumption (calories and macronutrients), and anthropometric and body composition variables (weight, body mass index, waist circumference, and body fat percentage). RESULTS: There were no statistically significant results between groups at the baseline regarding sociodemographic and clinical characteristics. Also, there was no significant interaction between time versus group for any of the variables studied. Treatment with tDCS was well tolerated and there were no serious adverse effects. CONCLUSIONS: In women affected by overweight and obesity with food cravings, 10 sessions of F4 (anodal) and F3 (cathodal) tDCS did not produce changes in eating behavior, food consumption, and anthropometric and body composition.

Altered Heart Rate Variability During Mobile Game Playing and Watching Self-Mobile Gaming in Individuals with Problematic Mobile Game Use: Implications for Cardiac Health.

Introduction: The surge in mobile gaming, fueled by smartphone and internet accessibility, lacks a comprehensive understanding of physiological changes during gameplay. Methods: This study, involving 93 participants (average age 21.75 years), categorized them into Problematic Mobile Gaming (PMG) and non-problematic Mobile Gaming (nPMG) groups based on Problematic Mobile Gaming Questionnaire (PMGQ) scores. The PMGQ is a 12-item scale developed in Taiwan to assess symptoms of problematic mobile gaming. The research delved into heart rate variability (HRV) alterations during real-time mobile gaming and self-gaming video viewing. Results: Results showed that the PMG group significantly presents a lower root mean square of successive differences (RMSSD), and High Frequency (lnHF) than does the nPMG group (F=4.73, p=0.03; F=10.65, p=0.002, respectively) at the baseline. In addition, the PMG group significantly displayed elevated HF and low-frequency to high-frequency (LF/HF) in the mobile-gaming (F=7.59, p=0.007; F=9.31, p=0.003) condition as well as in the watching self-gaming videos (F=9.75, p=0.002; F=9.02, p=0.003) than did the nPMG. Conclusion: The study suggests targeted interventions to mitigate autonomic arousal, offering a potential avenue to address adverse effects associated with problematic mobile gaming behavior. The PMG group displayed increased craving scores after real-time mobile gaming and watching self-gaming video excerpts, unlike the nPMG group. Elevated LF/HF ratios in frequent gaming cases heightened autonomic arousal, presenting challenges in relaxation after mobile gaming. These findings contribute to a nuanced understanding of the complex interplay between mobile gaming activities, physiological responses, and potential intervention strategies.

Exposure to preference-matched alcohol advertisements from national sports broadcasts increases short-term alcohol consumption inclinations in risky drinkers.

BACKGROUND: In Australia, sports broadcasting is afforded special alcohol advertising rights during daytime hours, which raises public health concerns, including short-term increases in alcohol consumption among the broad viewership of national sporting codes. METHODS: We conducted a content analysis across a sample of nationally televised finals matches (N = 16) from the Australian Football League (AFL) and the National Rugby League (NRL) to determine the prevalence of alcohol advertising video clips during these broadcasts. We also conducted an online experiment exposing participants (N = 345) to a randomly selected alcohol advertisement and measured the immediate effects on self-reported alcohol craving and drinking intentions. RESULTS: The prevalence of alcohol advertising video clips during AFL broadcasts was 3.9% and 1.8% for NRL. While, overall, alcohol advertisement video clip exposure did not impact craving or drinking intentions, a modest increase in craving was found for a subsample of risky drinking participants (N = 107) who also reported a preference for the specific alcoholic beverage being advertised. CONCLUSIONS: Video alcohol advertisements occurred less than 1 in 20 advertisements on average and exposure to alcohol advertising elicited a low, yet measurable, short-term increase in alcohol inclinations, among vulnerable adult drinkers when a desirable alcoholic beverage advertisement is viewed. SO WHAT?: Given that alcohol advertisements are most likely to increase consumption among risky drinkers, health messaging during sports broadcasts needs to specifically target these individuals.

Altered executive control network and default model network topology are linked to acute electronic cigarette use: A resting-state fNIRS study.

In recent years, electronic cigarettes (e-cigs) have gained popularity as stylish, safe, and effective smoking cessation aids, leading to widespread consumer acceptance. Although previous research has explored the acute effects of combustible cigarettes or nicotine replacement therapy on brain functional activities, studies on e-cigs have been limited. Using fNIRS, we conducted graph theory analysis on the resting-state functional connectivity of 61 male abstinent smokers both before and after vaping e-cigs. And we performed Pearson correlation analysis to investigate the relationship between alterations in network metrics and changes in craving. E-cig use resulted in increased degree centrality, nodal efficiency, and local efficiency within the executive control network (ECN), while causing a decrease in these properties within the default model network (DMN). These alterations were found to be correlated with reductions in craving, indicating a relationship between differing network topologies in the ECN and DMN and decreased craving. These findings suggest that the impact of e-cig usage on network topologies observed in male smokers resembles the effects observed with traditional cigarettes and other forms of nicotine delivery, providing valuable insights into their addictive potential and effectiveness as aids for smoking cessation.

The ReCoDe addiction research consortium: Losing and regaining control over drug intake-Findings and future perspectives.

Substance use disorders (SUDs) are seen as a continuum ranging from goal-directed and hedonic drug use to loss of control over drug intake with aversive consequences for mental and physical health and social functioning. The main goals of our interdisciplinary German collaborative research centre on Losing and Regaining Control over Drug Intake (ReCoDe) are (i) to study triggers (drug cues, stressors, drug priming) and modifying factors (age, gender, physical activity, cognitive functions, childhood adversity, social factors, such as loneliness and social contact/interaction) that longitudinally modulate the trajectories of losing and regaining control over drug consumption under real-life conditions. (ii) To study underlying behavioural, cognitive and neurobiological mechanisms of disease trajectories and drug-related behaviours and (iii) to provide non-invasive mechanism-based interventions. These goals are achieved by: (A) using innovative mHealth (mobile health) tools to longitudinally monitor the effects of triggers and modifying factors on drug consumption patterns in real life in a cohort of 900 patients with alcohol use disorder. This approach will be complemented by animal models of addiction with 24/7 automated behavioural monitoring across an entire disease trajectory; i.e. from a naïve state to a drug-taking state to an addiction or resilience-like state. (B) The identification and, if applicable, computational modelling of key molecular, neurobiological and psychological mechanisms (e.g., reduced cognitive flexibility) mediating the effects of such triggers and modifying factors on disease trajectories. (C) Developing and testing non-invasive interventions (e.g., Just-In-Time-Adaptive-Interventions (JITAIs), various non-invasive brain stimulations (NIBS), individualized physical activity) that specifically target the underlying mechanisms for regaining control over drug intake. Here, we will report on the most important results of the first funding period and outline our future research strategy.

Tackling addictive behaviors through memory suppression: A scoping review and perspective.

Forgetting is often viewed as a human frailty. However, over the years, it has been considered an adaptive process that allows people to avoid retrieval of undesirable memories, preventing them from suffering and discomfort. Evidence shows that the ability to suppress memories is affected by several psychopathological conditions characterized by persistent unwanted thoughts, including anxiety and posttraumatic stress disorders. Nevertheless, memory suppression (MS) mechanisms in addiction-a clinical condition characterized by recurrent drug-related thoughts that contribute to repeated drug use-have received little attention so far. Addiction theories reveal that drugs change behavior by working on memory systems, particularly on declarative memory, which is related to the retrieval and encoding of drug-related memories. In this review, the main behavioral and neurofunctional findings concerning the Think/No-Think task-an adaptation of the classical Go/No-Go tasks typically used to evaluate the suppression of motor response-are presented. We then show how the memory system can be involved in the craving or anticipation/preoccupation stage of the addiction cycle. Subsequently, the study of MS in the context of addictive behaviors is highlighted as a promising approach for gaining knowledge about the mechanisms contributing to the continuation of addiction. Finally, we discuss how interventions aiming to strengthen this ability could impact the anticipation/preoccupation stage by (i) reducing the accessibility of drug-related memories, (ii) decreasing craving and attention toward drug-related stimuli, and (iii) improving overall inhibition abilities. In conclusion, this review aims to illustrate how the study of MS may be a valuable approach to enhance our understanding of substance use disorders by unveiling the underlying cognitive and neural mechanisms involved, which could have important implications for addiction treatment.

The mediating role of trait impulsivity in the relation between cue-induced craving and functional connectivity within the salience network among abstinent patients with methamphetamine use disorder.

Given the widespread use and relapse of methamphetamine (METH), it has caused serious public health burdens globally. However, the neurobiological basis of METH addiction remains poorly understood. Therefore, this study aimed to use magnetic resonance imaging (MRI) to investigate changes in brain networks and their connection to impulsivity and drug craving in abstinent individuals with METH use disorder (MUDs). A total of 110 MUDs and 55 age- and gender-matched healthy controls (HCs) underwent resting-state functional MRI and T1-weighted imaging scans, and completed impulsivity and cue-induced craving measurements. We applied independent component analysis to construct functional brain networks and multivariate analysis of covariance to investigate group differences in network connectivity. Mediation analyses were conducted to explore the relationships among brain-network functional connectivity (FC), impulsivity, and drug craving in the patients. MUDs showed increased connectivity in the salience network (SN) and decreased connectivity in the default mode network compared to HCs. Impulsivity was positively correlated with FC within the SN and played a completely mediating role between METH craving and FC within the SN in MUDs. These findings suggest alterations in functional brain networks underlying METH dependence, with SN potentially acting as a core neural substrate for impulse control disorders.

Small pouches, but high nicotine doses-nicotine delivery and acute effects after use of tobacco-free nicotine pouches.

Tobacco-free nicotine pouches are new nicotine products for oral consumption. They can contain very high nicotine amounts that have not been addressed with clinical studies yet. Thus, nicotine delivery, effects on craving, and side effects were assessed using pouches with up to 30 mg nicotine. In this single-center, five-arm, crossover study, 15 regular cigarette smokers consumed tobacco-free nicotine pouches from different brands with 6, 20, and 30 mg for 20 min. Comparators were nicotine-free pouches and tobacco cigarettes. At baseline and predefined time points over a study period of 240 min, plasma nicotine concentrations, effects on cigarette craving, and side effects were assessed. Cardiovascular parameters including arterial stiffness were measured using a MobilOGraph. Consumption of 30 mg nicotine pouches has led to a higher nicotine uptake compared with the cigarette (Cmax: 29.4 vs 15.2 ng/mL; AUC: 45.7 vs 22.1 ng/mL × h). Nicotine uptake in the acute phase was rapid during use of the 30 mg pouch and cigarette. Extraction rate of nicotine differed between pouches. Use of all products has reduced acute cigarette craving, even the nicotine-free pouch. During consumption of the cigarette and the pouches with 20 and 30 mg, heart rate increased about 27, 12, and 25 bpm, respectively. Parameters for arterial stiffness were elevated and all pouches have induced mouth irritations. The pouches with 30 mg nicotine had overall the strongest side effects and may induce addiction. As craving was also reduced by products with less nicotine, it is questionable whether such high nicotine contents should be allowed on the market. A limit of nicotine content is warranted. The nicotine release rate varies across products and needs to be known to estimate the nicotine delivery.

An Adaptation and Validation of Cocaine Craving Questionnaire for Malaysians Who Use Amphetamine-Type Stimulants.

Introduction: Cases of amphetamine-type stimulants (ATS) use have been increasing over the past decade. Cravings are considered a causal factor for recurrent relapses in ATS use cases. The absence of questionnaires measuring cravings for ATS in the local population necessitates the creation of one, especially considering the rising number of cases. Objective: This study aimed to adapt and validate the Cocaine Cravings Questionnaire into a questionnaire suitable for measuring cravings for ATS in the local population. Methodology: The original questionnaire was adapted by substituting "cocaine" with "ATS". The process involved a back-to-back translation, followed by a round of face and content validation. The participants included people who use drugs (PWUD) with a history of ATS use recruited from rehabilitation centers in Malaysia. A set of questionnaires consisting of demographic items and the adapted ATS Cravings Questionnaire (ATS-CQ) were given. Results: This cross-sectional study recruited a total of 205 PWUD, mostly single men, with a mean age of 33.32 (s.d.=13.14). The mean age of ATS initiation was 22.89 (s.d.=9.39), with a median duration of ATS use of 60 months (IQR=24.00, 120.00). The adapted questionnaire received a good score for content validation. Unlike the original, this adapted version was found to have only three factors showing good internal consistency, ranging from 0.707 to 0.918 for all three factors. Test-retest reliability also showed good results, with an interclass correlation coefficient of 0.875 (95% CI=0.835, 0.905). Conclusion: The translated ATS-CQ has been finalized and deemed valid and reliable for use among Malaysian substance users to measure ATS cravings.

Advancements in addressing drug dependence: A review of promising therapeutic strategies and interventions.

Substance dependence represents a pervasive global concern within the realm of public health. Presently, it is delineated as a persistent and recurrent neurological disorder stemming from drug-triggered neuroadaptations in the brain's reward circuitry. Despite the availability of various therapeutic modalities, there has been a steady escalation in the mortality rate attributed to drug overdoses. Substantial endeavors have been directed towards the exploration of innovative interventions aimed at mitigating cravings and drug-induced repetitive behaviors. Within this review, we encapsulate the most auspicious contemporary treatment methodologies, accentuating meta-analyses of efficacious pharmacological and non-pharmacological approaches: including gabapentin, topiramate, prazosin, physical exercise regimens, and cerebral stimulation techniques.

Transcranial magnetic stimulation for methamphetamine use disorder: A scoping review within the neurocircuitry model of addiction.

The use of methamphetamine in the United States is increasing, contributing now to the "fourth wave" in the national opioid epidemic crisis. People who suffer from methamphetamine use disorder (MUD) have a higher risk of death. No pharmacological interventions are approved by the FDA and psychosocial interventions are only moderately effective. Transcranial Magnetic Stimulation (TMS) is a relatively novel FDA-cleared intervention for the treatment of Major Depressive Disorder (MDD) and other neuropsychiatric conditions. Several lines of research suggest that TMS could be useful for the treatment of addictive disorders, including MUD. We will review those published clinical trials that show potential effects on craving reduction of TMS when applied over the dorsolateral prefrontal cortex (DLPFC) also highlighting some limitations that affect their generalizability and applicability. We propose the use of the Koob and Volkow's neurocircuitry model of addiction as a frame to explain the brain effects of TMS in patients with MUD. We will finally discuss new venues that could lead to a more individualized and effective treatment of this complex disorder including the use of neuroimaging, the exploration of different areas of the brain such as the frontopolar cortex or the salience network and the use of biomarkers.

Retinoic acid-mediated homeostatic plasticity in the nucleus accumbens core contributes to incubation of cocaine craving.

RATIONALE: Incubation of cocaine craving refers to the progressive intensification of cue-induced craving during abstinence from cocaine self-administration. We showed previously that homomeric GluA1 Ca2+-permeable AMPARs (CP-AMPAR) accumulate in excitatory synapses of nucleus accumbens core (NAcc) medium spiny neurons (MSN) after ∼1 month of abstinence and thereafter their activation is required for expression of incubation. Therefore, it is important to understand mechanisms underlying CP-AMPAR plasticity. OBJECTIVES: We hypothesize that CP-AMPAR upregulation represents a retinoic acid (RA)-dependent form of homeostatic plasticity, previously described in other brain regions, in which a reduction in neuronal activity disinhibits RA synthesis, leading to GluA1 translation and CP-AMPAR synaptic insertion. We tested this using viral vectors to bidirectionally manipulate RA signaling in NAcc during abstinence following extended-access cocaine self-administration. RESULTS: We used shRNA targeted to the RA degradative enzyme Cyp26b1 to increase RA signaling. This treatment accelerated incubation; rats expressed incubation on abstinence day (AD) 15, when it is not yet detected in control rats. It also accelerated CP-AMPAR synaptic insertion measured with slice physiology. CP-AMPARs were detected in Cyp26b1 shRNA-expressing MSN, but not control MSN, on AD15-18. Next, we used shRNA targeted to the major RA synthetic enzyme Aldh1a1 to reduce RA signaling. In MSN expressing Aldh1a1 shRNA, synaptic CP-AMPARs were reduced in late withdrawal (AD42-60) compared to controls. However, we did not detect an effect of this manipulation on incubated cocaine seeking (AD40). CONCLUSIONS: These findings support the hypothesis that increased RA signaling during abstinence contributes to CP-AMPAR accumulation and incubation of cocaine craving.

Exploring the Potential Impact of GLP-1 Receptor Agonists on Substance Use, Compulsive Behavior, and Libido: Insights from Social Media Using a Mixed-Methods Approach.

Glucagon-like peptide-1 (GLP-1) is involved in a range of central and peripheral pathways related to appetitive behavior. Hence, this study explored the effects of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) on substance and behavioral addictions, including alcohol, caffeine, nicotine, cannabis, psychostimulants, compulsive shopping, and sex drive/libido. Data were collected from various social platforms. Keywords related to GLP-1 RAs and substance/behavioral addiction were used to extract relevant comments. The study employed a mixed-methods approach to analyze online discussions posted from December 2019 to June 2023 and collected using a specialized web application. Reddit entries were the focus here due to limited data from other platforms, such as TikTok and YouTube. A total of 5859 threads and related comments were extracted from six subreddits, which included threads about GLP-1 RAs drugs and associated brand names. To obtain relevant posts, keywords related to potential substance use and compulsive behavior were selected. Further analysis involved two main steps: (1) manually coding posts based on users' references to the potential impact of GLP-1 RAs on substance use and non-substance habits, excluding irrelevant or unclear comments; (2) performing a thematic analysis on the dataset of keywords, using AI-assisted techniques followed by the manual revision of the generated themes. Second, a thematic analysis was performed on the keyword-related dataset, using AI-assisted techniques followed by the manual revision of the generated themes. In total, 29.75% of alcohol-related; 22.22% of caffeine-related; and 23.08% of nicotine-related comments clearly stated a cessation of the intake of these substances following the start of GLP-1 RAs prescription. Conversely, mixed results were found for cannabis intake, and only limited, anecdotal data were made available for cocaine, entactogens, and dissociative drugs' misuse. Regarding behavioral addictions, 21.35% of comments reported a compulsive shopping interruption, whilst the sexual drive/libido elements reportedly increased in several users. The current mixed-methods approach appeared to be a useful tool in gaining insight into complex topics such as the effects of GLP-1 RAs on substance and non-substance addiction-related disorders; some GLP-1 RA-related mental health benefits could also be inferred from here. Overall, it appeared that GLP-1 RAs may show the potential to target both substance craving and maladaptive/addictive behaviors, although further empirical research is needed.

Evaluation of a digital tool for detecting stress and craving in SUD recovery: An observational trial of accuracy and engagement.

BACKGROUND: Digital health interventions offer opportunities to expand access to substance use disorder (SUD) treatment, collect objective real-time data, and deliver just-in-time interventions: however implementation has been limited. RAE (Realize, Analyze, Engage) Health is a digital tool which uses continuous physiologic data to detect high risk behavioral states (stress and craving) during SUD recovery. METHODS: This was an observational study to evaluate the digital stress and craving detection during outpatient SUD treatment. Participants were asked to use the RAE Health app, wear a commercial-grade wrist sensor over a 30-day period. They were asked to self-report stress and craving, at which time were offered brief in-app de-escalation tools. Supervised machine learning algorithms were applied retrospectively to wearable sensor data obtained to develop group-based digital biomarkers for stress and craving. Engagement was assessed by number of days of utilization, and number of hours in a given day of connection. RESULTS: Sixty percent of participants (N=30) completed the 30-day protocol. The model detected stress and craving correctly 76 % and 69 % of the time, respectively, but with false positive rates of 33 % and 28 % respectively. All models performed close to previously validated models from a research grade sensor. Participants used the app for a mean of 14.2 days (SD 10.1) and 11.7 h per day (SD 8.2). Anxiety disorders were associated with higher mean hours per day connected, and return to drug use events were associated with lower mean hours per day connected. CONCLUSIONS: Future work should explore the effect of similar digital health systems on treatment outcomes and the optimal dose of digital interventions needed to make a clinically significant impact.

Nature-based experience in Venetian lagoon: Effects on craving and wellbeing in addict residential inpatients.

Introduction: It is known that exposure to the natural environment may positively modulate mental processes and behaviors; in particular, it can reduce stress, anxiety, and depressive symptoms. This suggests a potential integration of "nature experience" into the treatment for substance use disorder (SUD) since various types of addiction are associated with anxiety and depression. Considering that only one study has been reported to date in patients with alcohol use disorder, the effect of nature experience in SUD patients' needs to be further investigated. This study aimed to test the effects of exposure to a natural lagoon environment on craving and measures of wellbeing in SUD patients in comparison to exposure to an urban environment. Methods: Twenty-four SUD patients were divided into three groups of eight participants and exposed to two walking sessions (interspersed with a 1-week wash-out period) in a natural environment typical of the Venetian lagoon, an Urban walk, or staying at the residential center based on a Latin-square design. Before and after each session, drug craving, mood, wellbeing, agency, openness to the future, and restorativeness were assessed. Results: The Nature walk significantly decreased craving in participants compared to their pre-walk values, and compared to craving after the Urban walk, with the latter significantly increased vs. pre-walk values. The Nature walk significantly decreased negative mood and increased wellbeing and agency. Openness to the future and restorativeness measures showed significant improvement after the Nature walk compared to the Urban walk. On the other hand, craving scores after the Urban Walk positively correlated with negative mood and a Sense of Negative Agency values and negatively correlated with wellbeing scores. Discussion: Our results confirm that "nature experience" may improve mood, wellbeing, attention, stress relief, openness, and sense of being active in SUD patients. Moreover, we also showed a specific effect on drug craving-a key symptom of SUD.