Modulation of dlPFC function and decision-making capacity by repetitive transcranial magnetic stimulation in methamphetamine use disorder.

This study explores the impact of repetitive transcranial magnetic stimulation (rTMS) on decision-making capabilities in individuals with methamphetamine use disorder (MUD), alongside potential underlying psychological mechanisms. Employing the Iowa Gambling Task (IGT) and computational modeling techniques, we assessed the decision-making processes of 50 male MUD participants (24 underwent rTMS treatment, 26 received no treatment) and 39 healthy controls (HC). We compared pre- and post-rTMS treatment alterations in the left dorsolateral prefrontal cortex (dlPFC). Results revealed inferior performance in the IGT among the MUD group, characterized by aberrant model parameters in the Value-Plus-Perseverance (VPP) model, including heightened learning rate, outcome sensitivity, and reinforcement learning weight, alongside diminished response consistency and loss aversion. RTMS treatment demonstrated efficacy in reducing craving scores, enhancing decision-making abilities, and partially restoring normalcy to certain model parameters in the MUD cohort. Nonetheless, no linear relationship between changes in model parameters and craving was observed. These findings lend support to the somatic marker hypothesis, implicating the dlPFC in the decision-making deficits observed in MUD, with rTMS potentially ameliorating these deficits by modulating the function of these brain regions. This study not only offers novel insights and methodologies for MUD rehabilitation but also underscores the necessity for further research to corroborate and refine these findings. Trial Registration www.chictr.org.cn Identifier: No. ChiCTR17013610.

Volitionally Regulated Breathing with Prolonged Expiration Influences Food Craving and Impulsivity.

INTRODUCTION: Previously, an intervention involving volitional slow breathing reduced trait food craving with protective effects on cardiac vagal activity (CVA). Breathing with a low inspiration-to-expiration (i/e) ratio also increases CVA. High CVA was separately associated with low unregulated eating and lesser impulsivity. Hence, the present study assessed breathing with a low i/e for effects on state food craving, hunger and satiety, state impulsivity, and heart rate variability (HRV) in healthy obese persons. METHODS: Forty obese persons were randomized to two groups. The intervention group (mean age ± SD, 41.15 ± 12.63, M:F, 10:10) practiced metronome-regulated breathing with low i/e at 12 breaths per minute (expiration 72% of total breath duration) and attained expiration 55.8% of total breath duration, while the active control group (mean age ± SD, 44.45 ± 11.06, M:F, 13:07) sat motionless and directed their gaze and awareness to the stationary metronome without modifying their breath consciously. The HRV was recorded before, during, and after breathing intervention (or control) (standard limb lead I, acquisition at 2,000 Hz, with an LF filter = 0.5 Hz and HF filter = 50 Hz). Time-domain and frequency-domain HRV parameters were obtained with Kubios software. State food craving, and hunger and satiety were recorded before and after the intervention/control. RESULTS: The intervention group decreased total state food craving scores and the sub-domains (i.e., desire to eat, positive reinforcement, lack of control and hunger), increased current satisfaction with food, decreased total state impulsivity (repeated measures ANOVA, p < 0.05 in all cases), increased HF-HRV and RMSSD (linear mixed model analyses with age and gender as fixed factors; p < 0.05 in all cases) during the intervention compared to the preceding baseline. The intervention group also showed an increase in positive mood and a decrease in aroused and negative mood states. CONCLUSION: Changes in state food craving and impulsivity could be related to an increase in HRV or to changes in subjective relaxation and positive mood or to both.

Connecting self-report and instrumental behavior during incubation of food craving in humans.

Incubation of craving is a phenomenon describing the intensification of craving for a reward over extended periods of abstinence from reinforcement. Animal models use instrumental markers of craving to reward cues to examine incubation, while human paradigms rely on subjective self-reports. Here, we characterize an animal-inspired, novel human paradigm that showed strong positive relationships between self-reports and instrumental markers of craving for favored palatable foods. Further, we found consistent nonlinear relationships with time since last consumption and self-reports, and preliminary patterns between time and instrumental responses. These findings provide a novel approach to establishing an animal-inspired human model of incubation.

Identifying the role of (dis)inhibition in the vicious cycle of substance use through ecological momentary assessment and resting-state fMRI.

Functional inhibition is known to improve treatment outcomes in substance use disorder (SUD), potentially through craving management enabled by underlying cerebral integrity. Whereas treatment is challenged by a multitude of substances that patients often use, no study has yet unraveled if inhibition and related cerebral integrity could prevent relapse from multiples substances, that is, one's primary drug of choice and secondary ones. Individuals with primary alcohol, cannabis, or tobacco use disorders completed intensive Ecological Momentary Assessment (EMA) coupled with resting-state functional MRI (rs-fMRI) to characterize the extent to which inhibition and cerebral substrates interact with craving and use of primary and any substances. Participants were 64 patients with SUD and 35 healthy controls who completed one week EMA using Smartphones to report 5 times daily their craving intensity and substance use and to complete Stroop inhibition testing twice daily. Subsamples of 40 patients with SUD and 34 control individuals underwent rs-fMRI. Mixed Model Analysis revealed that reported use of any substance by SUD individuals predicted later use of any and primary substance, whereas use of the primary substance only predicted higher use of that same substances. Craving and inhibition level independently predicted later use but did not significantly interact. Preserved inhibition performance additionally influenced use indirectly by mediating the link between subsequent uses and by being linked to rs-fMRI connectivity strength in fronto-frontal and cerebello-occipital connections. As hypothesized, preserved inhibition performance, reinforced by the integrity of inhibitory neurofunctional substrates, may partake in breaking an unhealthy substance use pattern for a primary substance but may not generalize to non-target substances or to craving management.

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.

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.

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.

Analysis of addiction craving onset through natural language processing of the online forum Reddit.

AIMS: Alcohol cravings are considered a major factor in relapse among individuals with alcohol use disorder (AUD). This study aims to investigate the frequency and triggers of cravings in the daily lives of people with alcohol-related issues. Large amounts of data are analyzed with Artificial Intelligence (AI) methods to identify possible groupings and patterns. METHODS: For the analysis, posts from the online forum "stopdrinking" on the Reddit platform were used as the dataset from April 2017 to April 2022. The posts were filtered for craving content and processed using the word2vec method to map them into a multi-dimensional vector space. Statistical analyses were conducted to calculate the nature and frequency of craving contexts and triggers (location, time, social environment, and emotions) using word similarity scores. Additionally, the themes of the craving-related posts were semantically grouped using a Latent Dirichlet Allocation (LDA) topic model. The accuracy of the results was evaluated using two manually created test datasets. RESULTS: Approximately 16% of the forum posts discuss cravings. The number of craving-related posts decreases exponentially with the number of days since the author's last alcoholic drink. The topic model confirms that the majority of posts involve individual factors and triggers of cravings. The context analysis aligns with previous craving trigger findings related to the social environment, locations and emotions. Strong semantic craving similarities were found for the emotions boredom, stress and the location airport. The results for each method were successfully validated on test datasets. CONCLUSIONS: This exploratory approach is the first to analyze alcohol cravings in the daily lives of over 24,000 individuals, providing a foundation for further AI-based craving analyses. The analysis confirms commonly known craving triggers and even discovers new important craving contexts.

Neural Correlates of Stress and Alcohol Cue-Induced Alcohol Craving and of Future Heavy Drinking: Evidence of Sex Differences.

OBJECTIVE: Stress and alcohol cue reactivity are associated with poor treatment outcomes in alcohol use disorder (AUD), but sex-specific neural correlates of stress and alcohol cue-induced craving compared with neutral cue-induced craving and of heavy drinking outcomes in AUD have not been examined. Thus, this study prospectively examined these associations and assessed sex differences. METHODS: Treatment-seeking adults with AUD (N=77; 46 men and 31 women) completed a functional MRI task involving stress, alcohol, and neutral cue exposure with repeated assessments of alcohol craving. Most of these participants (N=72; 43 men and 29 women) then participated in an 8-week standardized behavioral AUD treatment program, during which the percentage of heavy drinking days was assessed. RESULTS: Significant increases in both stress and alcohol cue-induced craving relative to neutral cue-induced craving were observed, with a greater alcohol-neutral contrast in craving relative to the stress-neutral contrast among men and equivalent stress-neutral and alcohol-neutral contrasts in craving among women. Whole-brain voxel-based regression analyses showed craving-associated hyperactivation in the neutral condition, but hypoactive prefrontal (ventromedial and lateral prefrontal, supplementary motor, and anterior cingulate regions) and striatal responses during exposure to stressful images (stress-neutral contrast) and alcohol cues (alcohol-neutral contrast), with significant sex differences. Additionally, a higher percentage of heavy drinking days was associated with hypoactivation of the subgenual anterior cingulate cortex and the bed nucleus of the stria terminalis in the stress-neutral contrast among women, hyperactivation of the hypothalamus in the stress-neutral contrast among men, and hyperactivation of the hippocampus in the alcohol-neutral contrast among men. CONCLUSIONS: Sex differences in stress- and alcohol cue-induced responses in the cortico-striatal-limbic network related to subjective alcohol craving and to heavy drinking indicated that distinct brain circuits underlie alcohol use outcomes in women and men. These findings underscore the need for sex-specific therapeutics to address this neural dysfunction effectively.

The Effectiveness of Transcranial Direct Current Stimulation (tDCS) in Binge Eating Disorder (BED)-Review and Insight into the Mechanisms of Action.

INTRODUCTION: Binge eating disorder (BED) is the most common eating disorder among those contributing to the development of obesity, and thus acts as a significant burden on the lives and health of patients. It is characterized by complex neurobiology, which includes changes in brain activity and neurotransmitter secretion. Existing treatments are moderately effective, and so the search for new therapies that are effective and safe is ongoing. AIM AND METHODS: This review examines the use of transcranial direct current stimulation (tDCS) in the treatment of binge eating disorder. Searches were conducted on the PubMed/Medline, Research Gate, and Cochrane databases. RESULTS: Six studies were found that matched the review topic. All of them used the anodal stimulation of the right dorsolateral prefrontal cortex (DLPFC) in BED patients. tDCS proved effective in reducing food cravings, the desire to binge eat, the number of binging episodes, and food intake. It also improved the outcomes of inhibitory control and the treatment of eating disorder psychopathology. The potential mechanisms of action of tDCS in BED are explained, limitations in current research are outlined, and recommendations for future research are provided. CONCLUSIONS: Preliminary evidence suggests that the anodal application of tDCS to the right DLPFC reduces the symptoms of BED. However, caution should be exercised in the broader use of tDCS in this context due to the small number of studies performed and the small number of patients included. Future studies should incorporate neuroimaging and neurophysiological measurements to elucidate the potential mechanisms of action of tDCS in BED.

Mindfulness Meditation Training Reduces Gaming Cravings by Reshaping the Functional Connectivity Between the Default Mode Network and Executive Control-Related Brain Regions.

BACKGROUND: Internet gaming disorder (IGD) can lead to psychological problems and cause behavioral problems in individuals. Traditional interventions have been ineffective in treating IGD. Meanwhile, mindfulness meditation (MM) is an emerging method that has proven to be effective for treating psychiatric disorders. In this study, MM was used to intervene in IGD and to explore its neural mechanism. METHODS: Eighty participants were recruited through advertisements. Eventually, 61 completed the 1-month training (MM group, n = 31; progressive muscle relaxation [PMR] group, n = 30), including a pretest, 8 training sessions, and a posttest. Regional homogeneity and degree centrality were calculated, and the tests (pre- and post-) and group (MM and PMR) analysis of variance was performed. The overlapping results were obtained as region of interest for functional connectivity (FC) analyses. Behavioral data and neurotransmitter availability maps were correlated with FC. RESULTS: Compared with PMR, MM decreased the severity of addiction and game craving in IGD. Brain imaging results showed that the FC between and within the executive control and default mode networks/reward-related regions were enhanced. Significant negative correlations were observed between FC and dopamine receptor D2, dopamine transporter, and vesicular acetylcholine transporter. Significant positive correlations were observed between FCs and serotonin and aminobutyric acid receptors. CONCLUSIONS: This study confirmed the effectiveness of MM in treating IGD. MM altered the default mode and enhanced top-down control over game cravings. These findings were revealed by the correlations between brain regions and behavioral and biochemical effects. The results show the neural mechanism of MM in reducing IGD and lay the foundation for future research.

Evidence that personalized racial stress procedures elicit a stress response and increases alcohol craving among Black adults with alcohol use disorder: A laboratory pilot study.

BACKGROUND: The objective of this study was to pilot test newly developed personalized imagery procedures to investigate the impact of racial stress on alcohol craving and emotional and physiological response in Black adults with alcohol use disorder (AUD). METHODS: Twenty Black adults (45% women, meanage=37.05, SDage=13.19) with AUD participated in two sessions. In the first, participants described a stressful personal event involving their race and a neutral relaxing situation and these descriptions were used to develop scripts for the subsequent laboratory exposure session. The second session was an experimental provocation session in which participants reported on alcohol craving and emotional response before and after imagined exposure to stress and neutral conditions using personalized racial stress and neutral/relaxing scripts. Conditions were randomized and counterbalanced across subjects, and heart rate and blood pressure were assessed before and after each image. RESULTS: Alcohol craving and negative emotions significantly increased, and positive emotions decreased following the racial stress script relative to the neutral/relaxing script. We found no differences in physiological response. Exploratory analyses found that increase in alcohol craving was correlated with racial identity exploration but not racial identity commitment, men reported greater reductions in anger than women in the neutral condition only, and income was correlated with fear in the racial stress condition only. CONCLUSIONS: This study provides evidence that personalized racial stress procedures elicit a stress response and increases alcohol craving and emotional response but not physiological response among Black adults with AUD. These findings warrant replication in a larger study.

Can period-related symptoms predict menstrual manipulation among Australian female cyclists?

This study explored the extent of menstrual manipulation and its associated impact on period-related symptoms and training disruptions in Australian Female Cyclists. 205 female cyclists, from recreational to elite level, participated in an online "Female Cyclist Questionnaire (FCQ)". The FCQ utilised a series of validated questionnaires to obtain demographic information and menstrual function of the respondents, and to investigate their menstrual manipulation habits and perceptions on how their period-related symptoms affected their well-being, mood, energy and training tolerance. More than 80% of the cyclists reported that their period-related symptoms impacted upon training and 41% made training adjustments based on these symptoms. Two-thirds of respondents thought their training should be phase-controlled yet only half discussed their hormonal cycles with their coaches. Menstrual manipulation was predicted by reduced "workout tolerance" in these cyclists (odds ratio = 0.632). Half of the respondents reported compromised ability to tolerate high-intensity interval training with period-related symptoms. Period pain, increased irritability, lower energy levels and more sugar cravings were commonly reported but did not predict menstrual manipulation. The data indicated that period-related symptoms are present in Australian female cyclists across all levels of participation. However, the perceived impact to training and subsequent behavioural changes varied among individuals.

Effects of bilateral tDCS over DLPFC on response inhibition, craving, and brain functional connectivity in Internet gaming disorder: A randomized, double-blind, sham-controlled trial with fMRI.

Background and aims: Impaired inhibitory control accompanied by enhanced craving is hallmark of addiction. This study investigated the effects of transcranial direct current stimulation (tDCS) on response inhibition and craving in Internet gaming disorder (IGD). We examined the brain changes after tDCS and their correlation with clinical variables. Methods: Twenty-four males with IGD were allocated randomly to an active or sham tDCS group, and data from 22 participants were included for analysis. Participants self-administered bilateral tDCS over the dorsolateral prefrontal cortex (DLPFC) for 10 sessions. Stop-signal tasks were conducted to measure response inhibition and participants were asked about their cravings for Internet gaming at baseline and post-tDCS. Functional magnetic resonance imaging data were collected at pre- and post-tDCS, and group differences in resting-state functional connectivity (rsFC) changes from the bilateral DLPFC and nucleus accumbens were examined. We explored the relationship between changes in the rsFC and behavioral variables in the active tDCS group. Results: A significant group-by-time interaction was observed in response inhibition. After tDCS, only the active group showed a decrease in the stop-signal reaction time (SSRT). Although craving decreased, there were no significant group-by-time interactions or group main effects. The anterior cingulate cortex (ACC) showed group differences in post- versus pre-tDCS rsFC from the right DLPFC. The rsFC between the ACC and left middle frontal gyrus was negatively correlated with the SSRT. Discussion and conclusion: Our study provides preliminary evidence that bilateral tDCS over the DLPFC improves inhibitory control and could serve as a therapeutic approach for IGD.

Wanting-liking dissociation and altered dopaminergic functioning: Similarities between internet gaming disorder and tobacco use disorder.

Background: Although internet gaming disorder (IGD) has been included in the DSM-5 for approximately 10 years, debate remains regarding its existence and classification. Methods: The current research incorporated three approaches. First, implicit association tests were used to examine for potential dissociation between wanting and liking in IGD. Second, brain features in wanting and liking circuits were tested and compared with tobacco use disorder (TUD) when performing a cue-craving task to explore the neural features of wanting and liking. Third, dopaminergic systems were investigated in IGD and TUD using neuromelanin-sensitive MRI. Results: The implicit association test results supported a wanting-liking dissociation in IGD participants. Functional MRI data suggested neural correlates underlying wanting-liking dissociation in IGD and TUD participants, with positive correlations suggesting greater dissociation with increasing addiction severity. Neuromelanin results suggest dopaminergic differences in IGD and TUD relative to healthy control participants. Conclusions: A wanting-liking dissociation in IGD participants suggests gaming motivations in IGD relating to incentive sensitization rather than hedonic responses. The neuromelanin-sensitive MRI results suggest dopaminergic involvement in IGD and TUD. The findings suggest similar brain-behaviour mechanisms for IGD and TUD based on an incentive-sensitization model for addiction, having implications for potential therapeutic strategies and policy-based interventions.

A randomized controlled trial of intermittent theta burst stimulation to the medial prefrontal cortex for tobacco use disorder: Clinical efficacy and safety.

OBJECTIVE: This study aimed to evaluate the clinical efficacy and safety of administering intermittent theta burst stimulation (iTBS) to the medial prefrontal cortex for tobacco use disorder. METHODS: A randomized sham-controlled trial was conducted, with 38 participants receiving 28 sessions of active (n=25) or sham (n=13) iTBS (2 sessions/day, 600 pulses/session, 110% resting motor threshold, AFz target) along with smoking cessation education (Forever Free © booklets) over 14 visits. Primary outcomes included self-reported cigarette consumption and abstinence, verified by urinary cotinine tests. Secondary outcomes included symptoms of tobacco use disorder, negative mood, and safety/tolerability. RESULTS: Both active and sham groups reported reduced cigarette consumption (ß = -0.12, p = 0.015), cigarette craving (ß = -0.16, p = 0.002), and tobacco withdrawal symptoms (ß = -0.05, p < 0.001). However, there were no significant time x group interaction effects for any measure. Similarly, the two groups had no significant differences in urinary cotinine-verified abstinence. Adverse events occurred with similar frequency in both groups. CONCLUSION: There were no differences in cigarette consumption between the active and sham iTBS groups, both groups decreased cigarette consumption similarly. Further research is needed to compare iTBS to standard high-frequency rTMS and explore the potential differences in efficacy. Despite limitations, this study contributes to experimental design considerations for TMS as a novel intervention for tobacco and other substance use disorders, emphasizing the need for a more comprehensive understanding of the stimulation parameters and target sites.

Hereditary and cortical morphological biomarker of sensitivity to reward in short-term withdrawal methamphetamine abusers.

Higher sensitivity to reward (SR) and weaker sensitivity to punishment (SP) construct the fundamental craving characteristics of methamphetamine abuse. However, few studies have appraised relationships between SR/SP (SR or SP) and cortical morphological alterations in methamphetamine abusers and whether hereditary factors take effects on SR/SP is unclear. Based on surface-based morphometric analysis, cortical discrepancy was investigated between 38 methamphetamine abusers and 37 healthy controls. Within methamphetamine abusers, correlation profiling was performed to discover associations among aberrant neuroimaging substrates, SR, SP, and craving. According to nine single nucleotide polymorphism sites of dopamine-related genes, we conducted univariate general linear model to find different effects of genotypes on cortical alterations and SR/SP/craving (SR, SP, or craving). Ultimately, mediation analyses were conducted among single nucleotide polymorphism sites, SR/SP/craving, and cortical morphological alterations to discover their association pathways. Compared to healthy controls, thinner cortices in inferior temporal gyrus, lateral orbitofrontal cortex, medial orbitofrontal cortex, inferior parietal lobule, and lateral occipital cortex in the left hemisphere were found in methamphetamine abusers (P < 0.05, family-wise error corrected). Cortical thickness in the inferior temporal gyrus was negatively correlated with SR scores. We found that rs1800497 A-containing genotypes had lower cortical thickness in the left inferior parietal lobule than the GG genotype. The rs5751876 had effects on SR scores. This study would provide convincing biomarkers for SR in methamphetamine abusers and offer potential genetic targets for personalizing relapse prevention.

Biological sex and hormonal contraceptive associations with drug cue reactivity in cannabis use disorder.

Biological sex differences in Cannabis Use Disorder (CUD) progression, cannabis withdrawal severity, and pharmacotherapy response have been reported, suggesting that CUD mechanisms may differ by sex. Drug cue reactivity is an established predictor of drug use behavior, but the literature on sex differences in drug cue reactivity is mixed, including in CUD. One possible moderator of sex differences in drug cue reactivity is hormonal contraceptive (HC) use. The aim of the present study was to test whether sex differences in neural cannabis cue reactivity and craving varied by female HC use in a CUD sample. As part of a larger study, 152 adults reporting frequent cannabis use completed a drug cue reactivity task during electrocenphalogram recording. Late positive potential (LPP) amplitude modulation by cannabis cues was used to measure neural cue reactivity. Craving after the cue reactivity task was also assessed. Males (n = 74) and naturally-cycling females (n = 26), who did not differ from each other, showed significantly greater LPP enhancement to cannabis vs. neutral cues compared to HC-using females (n = 52), an effect mostly driven by neutral cues. Craving was significantly higher in naturally-cycling but not HC-using females compared to males, but only in covariate-unadjusted analyses. Exploratory analyses of HC and menstrual phase characteristics indicate a progesterone-related mechanism may underlie HC effects on cannabis cue reactivity. The present study's results suggest that mixed findings on drug cue reactivity sex differences may be due to variability in HC use, which has implications for sex-specific models of CUD progression and treatment.

Intrinsic connectivity demonstrates a shared role of the posterior cingulate for cue reactivity in both gambling and cocaine use disorders.

Cue reactivity is relevant across addictive disorders as a process relevant to maintenance, relapse, and craving. Understanding the neurobiological foundations of cue reactivity across substance and behavioral addictions has important implications for intervention development. The present study used intrinsic connectivity distribution methods to examine functional connectivity during a cue-exposure fMRI task involving gambling, cocaine and sad videos in 22 subjects with gambling disorder, 24 with cocaine use disorder, and 40 healthy comparison subjects. Intrinsic connectivity distribution implicated the posterior cingulate cortex (PCC) at a stringent whole-brain threshold. Post-hoc analyses investigating the nature of the findings indicated that individuals with gambling disorder and cocaine use disorder exhibited decreased connectivity in the posterior cingulate during gambling and cocaine cues, respectively, as compared to other cues and compared to other groups. Brain-related cue reactivity in substance and behavioral addictions involve PCC connectivity in a content-to-disorder specific fashion. The findings suggesting that PCC-related circuitry underlies cue reactivity across substance and behavioral addictions suggests a potential biomarker for targeting in intervention development.

Molecular mechanisms involved in alcohol craving, IRF3, and endoplasmic reticulum stress: a multi-omics study.

Alcohol use disorder (AUD) is the most prevalent substance use disorder worldwide. Acamprosate and naltrexone are anti-craving drugs used in AUD pharmacotherapy. However, molecular mechanisms underlying their anti-craving effect remain unclear. This study utilized a patient-derived induced pluripotent stem cell (iPSC)-based model system and anti-craving drugs that are used to treat AUD as "molecular probes" to identify possible mechanisms associated with alcohol craving. We examined the pathophysiology of craving and anti-craving drugs by performing functional genomics studies using iPSC-derived astrocytes and next-generation sequencing. Specifically, RNA sequencing performed using peripheral blood mononuclear cells from AUD patients with extreme values for alcohol craving intensity prior to treatment showed that inflammation-related pathways were highly associated with alcohol cravings. We then performed a genome-wide assessment of chromatin accessibility and gene expression profiles of induced iPSC-derived astrocytes in response to ethanol or anti-craving drugs. Those experiments identified drug-dependent epigenomic signatures, with IRF3 as the most significantly enriched motif in chromatin accessible regions. Furthermore, the activation of IRF3 was associated with ethanol-induced endoplasmic reticulum (ER) stress which could be attenuated by anti-craving drugs, suggesting that ER stress attenuation might be a target for anti-craving agents. In conclusion, we found that craving intensity was associated with alcohol consumption and treatment outcomes. Our functional genomic studies suggest possible relationships among craving, ER stress, IRF3 and the actions of anti-craving drugs.