Open Label Pilot of Lorcaserin (a serotonin 2C-receptor agonist) for Cannabis Use Disorder.

Background And Objective: Cannabis Use Disorder (CUD) has no FDA approved treatment. Serotonin-2c (5HT2c) agonists have preclinical and human laboratory evidence for potential efficacy for CUD. We assessed the tolerability and effects of lorcaserin (5HT2c agonist) on CUD. Methods: In a 10-week, open label, uncontrolled trial, the tolerability of lorcaserin was tested in outpatients with CUD. Adverse events (AE) were assessed weekly. Cannabis use was assessed twice weekly by the Timeline follow-back and quantitative urine metabolites. Results: 17 participants enrolled, and 14 received medication. Participants' average age was 35 years; majority were male (N=12). The medication was well tolerated in males. There were no serious adverse events (SAE). The most common AE's were headache/migraine (N=4, all females), anorexia (N=3), and irritability (N=2). Participants decreased their frequency of cannabis use significantly (p < 0.001), adjusted for baseline use. By the end of the trial, participants decreased by 1.76 (SE=0.47) cannabis using days/week. Average daily amount of cannabis and urine THC metabolite levels did not change significantly. Conclusions: Lorcaserin was well tolerated in males but not females suggesting possible sex differences. Future trials of other 5HT2c agonists (lorcaserin was withdrawn at the request of the FDA) should consider longer dose titration phases. Trial Registration: NCT02932215.

Open label trial of lofexidine-assisted non-opioid induction onto naltrexone extended-release injection for opioid use disorder.

Background: Opioid use disorder (OUD) continues to be major public health problem in the US and innovative medication strategies are needed. The extended-release injectable formulation of naltrexone (ER-NTX), an opioid receptor antagonist, is an effective treatment for OUD, but the need for an opioid-free period during the induction phase of treatment is a barrier to treatment success, particularly in the outpatient setting. Lofexidine, an alpha-2-adrenergic agonist, is an effective treatment for opioid withdrawal.Objectives: To evaluate the feasibility, safety, and tolerability of lofexidine for facilitating induction onto ER-NTX in the management of OUD.Methods: In an open-label, uncontrolled, 10-week outpatient clinical trial, 20 adults (four women) with OUD were treated with a fixed-flexible dosing strategy (maximum 0.54 mg 4×/daily) of lofexidine for up to 10 days to manage opioid withdrawal prior to receiving ER-NTX. The COVID-19 pandemic resulted in a modification of the study methods after enrolling 10 participants who attended all visits in person. The second group of 10 participants attended most induction period visits remotely.Results: Overall, 10 of the 20 participants (50%) achieved the primary outcome by receiving the first ER-NTX injection. Rates of induction success did not differ by the presence of fentanyl or remote visit attendance, although the small sample size provided limited statistical power. Six out of 20 participants (30%) initiated on lofexidine required dose adjustments. There were no study-related serious adverse events.Conclusions: This study provides preliminary evidence supporting the feasibility of inducting individuals with OUD onto ER-NTX using lofexidine.

Drinking reduction during cognitive behavioral therapy for alcohol use disorder is associated with a reduction in anterior insula-bed nucleus of the stria terminalis resting-state functional connectivity.

BACKGROUND: Connectivity between the anterior insula (AI) and the bed nucleus of the stria terminalis (BNST) may play a role in negative emotions that drive compulsive drinking in patients with alcohol use disorder (AUD). We hypothesized that reductions in drinking during cognitive behavioral therapy (CBT), an effective treatment that teaches regulation (coping) skills for managing negative emotions during abstinence, would be associated with reductions in resting-state functional connectivity (RSFC) between the AI and the BNST. METHODS: We included 18 patients with a Diagnostic and Statistical Manual of Mental Disorders, fifth edition diagnosis of AUD who were (1) seeking treatment and (2) drinking heavily at baseline. We measured RSFC as Pearson's correlation between the BNST and multiple regions of interest in the insula at baseline and after completion of 12 weeks of a single-arm clinical trial of outpatient CBT. We also assessed the number of heavy drinking days over the previous 28 days (NHDD) at both time points. We used 1-sample t-tests to evaluate AI-BNST RSFC at baseline, paired t-tests to evaluate changes in AI-BNST RSFC from pre-CBT to post-CBT, and linear regression to evaluate the relationship between changes in AI-BNST RSFC and NHDD. RESULTS: We found a significant positive RSFC between the AI and the BNST at baseline (p = 0.0015). While there were no significant changes in AI-BNST RSFC from pre- to post-CBT at the group level (p = 0.42), we found that individual differences in reductions in AI-BNST RSFC from pre- to post-CBT were directly related to reductions in NHDD from pre- to post-CBT (r = 0.73, p = 0.0008). CONCLUSIONS: These findings provide preliminary evidence that reduced AI-BNST RSFC may be a mechanism of drinking reduction in AUD and that AI-BNST RSFC may be a target for CBT and possibly other treatments.

Open-label trial of a single-day induction onto buprenorphine extended-release injection for users of heroin and fentanyl.

BACKGROUND AND OBJECTIVES: Fentanyl and other highly potent synthetic opioids are the leading cause of opioid overdose deaths in the United States. METHODS: This study was an open-label, uncontrolled 12-week outpatient clinical trial to test the feasibility of a single-day induction onto extended-release buprenorphine (BXR) injection treatment for five adults (N = 5) with opioid use disorder using heroin-containing fentanyl. Participants were planned to receive three monthly BXR injections (300, 300, and 100 mg). RESULTS: After receiving 24 mg sublingual buprenorphine (SL-BUP), all five participants received the BXR 300 mg injection on the first day of induction. All five participants were retained for the full 3-month study period postinduction and received all three scheduled BXR injections. DISCUSSION AND CONCLUSION: This study provides preliminary evidence supporting the feasibility of inducting users of heroin-containing fentanyl onto BXR 300 mg in a single day. SCIENTIFIC SIGNIFICANCE: The ability to administer a long-acting injection of BXR that assures therapeutic serum levels for a month on the first day of treatment contact is a promising development for the treatment of OUD.

An open-label pilot study of pregabalin pharmacotherapy for alcohol use disorder.

Background: There is a need for alcohol use disorder (AUD) pharmacotherapy that can be administered to actively drinking outpatients. Pregabalin, a gabapentoid anticonvulsant, has preliminary evidence supporting effects on alcohol withdrawal and AUD.Objectives: To evaluate the safety, tolerability, and optimal dosing of pregabalin for treating AUD.Methods: In an open-label, 8-week, outpatient trial of eighteen adults (nine women) with AUD, participants were titrated to 600 mg/day (or the maximum tolerated dose) over 3 weeks and then maintained for 5 weeks.Results: The majority (11/14, 78.6%) of participants with at least one-week of medication exposure achieved a maximum dose of 600 mg/day. Mean retention was 6.8 weeks (SD = 2.6). Eighty percent (12/15) of participants with post-enrollment data reported any adverse effects during the trial; and for those reporting adverse effects the most common were drowsiness (33.3%, 4/12), and fogginess (25%, 3/12), dizziness (25%, 3/12), and insomnia (25%, 3/12). Two participants discontinued study medication due to adverse effects and one had a dose reduction. Mean Heavy Drinking Days (HDD)/week decreased significantly by 3.43 days (SD = 2.47; median (IQR) = 4.00 (1.00 to 5.50)); Wilcoxon signed rank test statistic ((S) = 49.5, p = .0006). Mean proportion of HDD significantly decreased on average by 48.7% (SD = 35.1%; median (IQR) = 57.1% (14.3% to 78.6%)). The proportion of abstinent days increased significantly on average by 36.1% (SD = 35.0%; median (IQR) = 17.9% (14.3% to 75.0%); S = 49.5, p = .0005).Conclusions: Pregabalin treatment of AUD appears to be safe and well tolerated in doses up to 600 mg per day.Trial Registration: clinicaltrials.gov identifier: NCT03256253.

Case Series: Rapid Induction Onto Long Acting Buprenorphine Injection for High Potency Synthetic Opioid Users.

BACKGROUND AND OBJECTIVES: Highly potent synthetic opioids (HPSO) are increasingly responsible for opioid overdose deaths in the United States. METHODS: In an open-label, uncontrolled trial to test the feasibility of extended-release buprenorphine (BXR) injection treatment of heroin-using individuals with opioid use disorder testing positive for HPSO, participants were enrolled and began an induction with sublingual BXR (n = 5). During the induction, ancillary medications (clonidine, clonazepam, zolpidem, and prochlorperazine) were provided for breakthrough opioid withdrawal symptoms. RESULTS: Two participants received the BXR injection on the second day of the induction and three participants on the third day. DISCUSSION AND CONCLUSION: All five participants were retained at least 1-month postinduction. SCIENTIFIC SIGNIFICANCE: It may be feasible to provide BXR treatment to HPSO-positive heroin users rapidly to achieve clinical stabilization. (Am J Addict 2020;00:00-00).

Cognitive regulation of craving in alcohol-dependent and social drinkers.

BACKGROUND: Helping alcohol-dependent individuals to cope with, or regulate, cue-induced craving using cognitive strategies is a therapeutic goal of cognitive behavioral therapy (CBT) for alcohol dependence. An assumption that underlies this approach is that alcohol dependence is associated with deficits in such cognitive regulation abilities. To date, however, the ability to utilize such strategies for regulation of craving has never been tested in a laboratory setting. METHODS: Here we compared 19 non-treatment-seeking, alcohol-dependent drinkers (AD) to 21 social drinkers (SD), using a laboratory task that measured the ability to reduce cue-induced alcohol craving by thinking about long-term negative consequences of drinking, which is a specific cognitive regulation strategy that is taught in CBT. The task also assessed the ability to reduce food craving elicited by high-calorie food cues using a similar strategy. RESULTS: The reduction in craving when using this cognitive regulation strategy was approximately double in SD, compared to AD, for both alcohol and food cues. Furthermore, in SD but not AD, the ability to regulate cue-induced alcohol craving was correlated with the ability to regulate food craving. There were no significant correlations found between the ability to regulate cue-induced alcohol craving and a number of self-report measures related to severity of alcohol dependence, baseline craving, impulsivity, and general self-regulation ability, for either AD or SD. CONCLUSIONS: The results suggest that alcohol dependence is associated with deficits in cognitive regulation of cue-induced craving and that these deficits are not specific to the regulation of alcohol craving, but generalize to the regulation of other appetitive states, such as food craving. Future studies may use similar procedures to address the neural and cognitive processes that underlie such regulation deficits, as well as the effects of treatments such as CBT on these processes.

Extended-Release Mixed Amphetamine Salts for Comorbid Adult Attention-Deficit/Hyperactivity Disorder and Cannabis Use Disorder: A Pilot, Randomized Double-Blind, Placebo-Controlled Trial.

OBJECTIVE: To determine if treatment of co-occurring adult ADHD and Cannabis Use Disorder (CUD) with extended-release mixed amphetamine salts (MAS-ER) would be effective at improving ADHD symptoms and promoting abstinence. METHOD: A 12-week randomized, double-blind, two-arm pilot feasibility trial of adults with comorbid ADHD and CUD (n = 28) comparing MAS-ER (80 mg) to placebo. Main outcomes: ADHD: ≥30% symptom reduction, measured by the Adult ADHD Investigator Symptom Rating Scale (AISRS). CUD: Abstinence during last 2 observed weeks of maintenance phase. RESULTS: Overall, medication was well-tolerated. There was no significant difference in ADHD symptom reduction (MAS-ER: 83.3%; placebo: 71.4%; p = .65) or cannabis abstinence (MAS-ER: 15.4%; placebo: 0%; p = .27). MAS-ER group showed a significant decrease in weekly cannabis use days over time compared to placebo (p < .0001). CONCLUSIONS: MAS-ER was generally well-tolerated. The small sample size precluded a determination of MAS-ER's superiority reducing ADHD symptoms or promoting abstinence. Notably, MAS-ER significantly reduced weekly days of use over time.

Neural correlates of drinking reduction during a clinical trial of cognitive behavioral therapy for alcohol use disorder.

BACKGROUND: Cognitive behavioral therapy (CBT) is an effective treatment for alcohol use disorder (AUD). We hypothesized that the dorsolateral prefrontal cortex (DLPFC), a region implicated in cognitive control and goal-directed behavior, plays a role in behavior change during CBT by facilitating the regulation of craving (ROC). METHODS: Treatment-seeking participants with AUD (N = 22) underwent functional magnetic resonance imaging (fMRI) scanning both before and after a 12-week, single-arm trial of CBT, using an ROC task that was previously shown to engage the DLPFC. RESULTS: We found that both the percentage of heavy drinking days (PHDD) and the overall self-reported alcohol craving measured during the ROC task were significantly reduced from pre- to post-CBT. However, we did not find significant changes over time in either the ability to regulate craving or regulation-related activity in any brain region. We found a significant 3-way interaction between the effects of cue-induced craving, cue-induced brain activity and timepoint of assessment (pre- or post-CBT) on PHDD in the left DLPFC. Follow-up analysis showed that cue-induced craving was associated with cue-induced activity in the left DLPFC among participants who ceased heavy drinking during CBT, both at pre-CBT and post-CBT timepoints. No such associations were present at either timepoint among participants who continued to drink heavily. CONCLUSIONS: These results suggest that patients in whom DLPFC functioning is more strongly related to cue-induced craving may preferentially respond to CBT.

Neural correlates of drinking reduction during cognitive behavioral therapy for alcohol use disorder.

Cognitive behavioral therapy (CBT) is an effective treatment for alcohol use disorder (AUD). We hypothesized that the dorsolateral prefrontal cortex (DLPFC), a brain region implicated in cognitive control and goal-directed behavior, plays a role behavior change during CBT by facilitating regulation of craving. To examine this, treatment-seeking participants with AUD (N=22) underwent functional MRI scanning both before and after a 12-week single-arm trial of CBT, using a regulation of craving (ROC) fMRI task designed to measure an individual's ability to control alcohol craving and previously shown to engage the DLPFC. We found that both the number of heavy drinking days (NHDD, the primary clinical outcome) and the self-reported alcohol craving measured during the ROC paradigm were significantly reduced from pre- to post-CBT [NHDD: t=15.69, p<0.0001; alcohol craving: (F(1,21)=16.16; p=0.0006)]. Contrary to our hypothesis, there was no change in regulation effects on self-reported craving over time (F(1,21)=0.072; p=0.79), nor was there was a significant change in regulation effects over time on activity in any parcel. Searching the whole brain for neural correlates of reductions in drinking and craving after CBT, we found a significant 3-way interaction between the effects of cue-induced alcohol craving, cue-induced brain activity and timepoint of assessment (pre- or post-CBT) on NHDD in a parcel corresponding to area 46 of the right DLPFC (ß=-0.37, p=0.046, FDR corrected). Follow-up analyses showed that reductions in cue-induced alcohol craving from pre- to post-CBT were linearly related to reductions in alcohol cue-induced activity in area 46 only among participants who ceased heavy drinking during CBT (r=0.81, p=0.005) but not among those who continued to drink heavily (r=0.28, p=0.38). These results are consistent with a model in which CBT impacts heavy drinking by increasing the engagement of the DLPFC during cue-induced craving.

The hidden island of addiction: the insula.

Most prior research on the neurobiology of addiction has focused on the role of subcortical systems, such as the amygdala, the ventral striatum and mesolimbic dopamine system, in promoting the motivation to seek drugs. Recent evidence indicates that a largely overlooked structure, the insula, plays a crucial part in conscious urges to take drugs. The insula has been highlighted as a region that integrates interoceptive (i.e. bodily) states into conscious feelings and into decision-making processes that involve uncertain risk and reward. Here, we propose a model in which the processing of the interoceptive effects of drug use by the insula contributes to conscious drug urges and to decision-making processes that precipitate relapse.

Lorcaserin treatment for extended-release naltrexone induction and retention for opioid use disorder individuals: A pilot, placebo-controlled randomized trial.

BACKGROUND: Opioid Use Disorder (OUD) is a significant public health problem associated with severe morbidity and mortality. While effective pharmacotherapies are available, limitations exist with each. Induction onto extended-release naltrexone (XR-NTX) is more difficult than initiation of buprenorphine or methadone, even in inpatient settings, as it is recommended that patients remain abstinent for at least 7 days prior to initiating XR-NTX. The purpose of this trial was to determine if lorcaserin, a 5HT2c agonist, improves outpatient XR-NTX induction rates. METHODS: An 8-week trial beginning with a brief detoxification period and induction onto XR-NTX. Sixty participants with OUD were enrolled in the trial, with 49 participants at the initiation of detoxification randomized to lorcaserin or placebo for 39 days. Additionally, ancillary medications were provided. The primary outcome was the proportion of participants inducted onto the first XR-NTX injection. Secondary outcomes were withdrawal severity (measured by COWS and SOWS) prior to the first injection and the proportion of participants receiving the second XR-NTX injection. RESULTS: The proportion of participants inducted onto the first (lorcaserin: 36 %; placebo: 44 %; p = .67) and the second XR-NTX injection (lorcaserin: 27 %; placebo: 31 %; p = .77) was not significantly different between treatment arms. Prior to the first injection, withdrawal scores did not significantly differ between treatment arms over time (treatment*time interaction COWS: p = .11; SOWS: p = .39). CONCLUSIONS: Lorcaserin failed to improve outpatient XR-NTX induction rates. Although this study is small, the findings do not support the use of lorcaserin in promoting induction onto XR-NTX or in mitigating withdrawal symptoms.

Quetiapine treatment for cannabis use disorder.

BACKROUND: Pharmacotherapy for cannabis use disorder (CUD) is an important unmet public health need. METHODS: In a 12-week randomized double-blind placebo-controlled trial, the efficacy of quetiapine (300 mg nightly) for the treatment of CUD was tested in 130 outpatients. Weekly cannabis use was categorized into three groups: heavy use (5-7 days), moderate use (2-4 days) and light use (0-1 days). RESULTS: At baseline both groups were considered heavy users (using days per week: median = 7.0; interquartile range (IQR): 6.5-7.0; daily dollar value: median = $121.4; IQR: 73.8-206.3). The week-by-treatment interaction was marginally significant (χ2(2) = 5.56, P = .06). With each week, the odds of moderate compared to heavy use significantly increased in the quetiapine group (OR=1.17, P < .0001), but not significantly in the placebo group (OR=1.05, P = .16). The odds of light versus heavy use did not significantly differ over time (P = .12). Treatment was also associated with reduced cannabis withdrawal symptoms by 10.4% each week (95% CI: 8.9-11.8). No serious adverse events occurred during the study and no evidence of development of a movement disorder was detected. Adverse effects were not significantly different between the quetiapine and placebo treatment arms. CONCLUSIONS: The use of quetiapine to treat CUD was associated with an increased likelihood of heavy frequency use transitioning to moderate use, but not light use. The clinical significance of reductions in cannabis use, short of abstinence warrants further study.

Extended release mixed amphetamine salts and topiramate for cocaine dependence: A randomized clinical replication trial with frequent users.

BACKGROUND: Cocaine use disorder (CUD) remains a substantial public health problem with no clearly effective pharmacotherapy available. In a prior trial, combined amphetamine and topiramate treatment significantly reduced cocaine use among individuals demonstrating the most frequent use at baseline. This trial targeted such frequent users. METHODS: A double-blind, randomized placebo-controlled trial, testing the combination of mixed amphetamine salts extended-release (MAS-ER) and topiramate or placebo over a 12-week medication phase was conducted. The two-site outpatient trial included 127 adults (96 males) with CUD using at least 9 days in the prior month. MAS-ER was titrated to a maximum dose of 60 mg/day and topiramate to a maximum dose of 100 mg twice/day. The primary outcome was the proportion of individuals who achieved three consecutive abstinent weeks at the end of the study (EOS) as measured by urine toxicology and self-report. RESULTS: The proportion of participants achieving three abstinent weeks at the EOS was significantly (P = .03) larger in the treatment (14.1%) compared to the placebo group (0.0%), while controlling for baseline cocaine use, sex, current alcohol use disorder, and site. Of note, due to conservative cardiac safety-parameters a considerable number of individuals in the treatment group were discontinued from study medication (20.3%). CONCLUSIONS: While these findings provide further evidence that the combination of MAS-ER and topiramate is efficacious in promoting abstinence in CUD adults with frequent use it remains possible that the combination treatment is no more effective than either treatment alone. Despite this, the study provides a valuable "proof of concept."

Skin conductance responses are elicited by the airway sensory effects of puffs from cigarettes.

The airway sensations stimulated by smoking are an important source of hedonic impact (pleasure) for dependent smokers. The learning process by which these sensations become pleasurable is not well understood. The classical conditioning model predicts that airway sensory stimulation will elicit sympathetic arousal that is positively correlated with the hedonic impact that is elicited by airway sensory stimulation. To test this prediction, we measured skin conductance responses (SCRs) and subjective hedonic impact elicited by a series of individual puffs from nicotinized, denicotinized and unlit cigarettes. Nicotinized puffs elicited more subjective hedonic impact than denicotinized and unlit puffs partly as a result of the fact that they provided a greater level of airway sensory stimulation. We found that SCRs were not larger for nicotinized puffs than for denicotinized puffs, but that they were larger for both nicotinized and denicotinized puffs than for unlit puffs. We also found that the average SCR of a subject to denicotinized puffs was positively correlated with the average hedonic impact that a subject obtained from denicotinized puffs. Together, this suggests that SCR magnitude does not reflect within-subject variations in hedonic impact that are due to variations in the level of airway sensory stimulation, but that it does reflect individual differences in the amount of hedonic impact that is derived from a given level of airway sensory stimulation. The results of a post hoc correlation analysis suggest that these individual differences may have been due to variations in the prevailing urge to smoke. The implications of these findings for the classical conditioning model, as well as for other learning models, are discussed.

Basic emotions are associated with distinct patterns of cardiorespiratory activity.

The existence of specific somatic states associated with different emotions remains controversial. In this study, we investigated the profile of cardiorespiratory activity during the experience of fear, anger, sadness and happiness. ECG and respiratory activity was recorded in 43 healthy volunteers during the recall and experiential reliving of one or two potent emotional autobiographical episodes and a neutral episode. Univariate statistics indicated that the four emotions differed from each other and from the neutral control condition on several linear and spectral indices of cardiorespiratory activity. Dependent variables were further reduced to five physiologically meaningful factors using an exploratory principal component analysis (PCA). Multivariate analyses of variance and effect size estimates calculated on those factors confirmed the differences between the four emotion conditions. A stepwise discriminant analyses predicting emotions using the PCA factors led to a classification rate of 65.3% for the four emotions (chance=25%; p=0.001) and of 72.0-83.3% for pair-wise discrimination (chance=50%; p's<0.05). These findings may be considered preliminary in view of the small sample on which the multivariate approach has been applied. However, this study emphasizes the need to better characterize the multidimensional factors involved in cardio-respiratory regulation during emotion. These results are consistent with the notion that distinct patterns of peripheral physiological activity are associated with different emotions.

The airway sensory impact of nicotine contributes to the conditioned reinforcing effects of individual puffs from cigarettes.

Puffs from cigarettes are the fundamental unit of smoking reward. Here, we examined the extent to which reward from puffs can be derived from the airway sensory effect of nicotine, in the absence of a direct central nervous system effect of nicotine. We did this by assessing the self-reported reward obtained from individual puffs from nicotinized, denicotinized and unlit cigarettes within 7 s of inhalation, which is before nicotine had an opportunity to reach the brain. We also assessed the self-reported strength of airway sensations elicited by the puffs. We found that nicotinized puffs were rated as both stronger and more rewarding than denicotinized and unlit puffs. We also found that the extent to which nicotine elicited reward was directly correlated with the extent to which nicotine elicited airway sensations. This indicates that the airway sensory effects of nicotine contribute to the reward from puffs, above and beyond the reward derived from the airway sensory effects of non-nicotine constituents. These findings have implications for the interpretation of studies that use puffs as experimental units to examine nicotine reward. They also have implications for the use of denicotinized and low nicotine cigarettes as aids to smoking cessation.

Cognitive Neuroscience Approaches to Understanding Behavior Change in Alcohol Use Disorder Treatments.

Researchers have begun to apply cognitive neuroscience concepts and methods to study behavior change mechanisms in alcohol use disorder (AUD) treatments. This review begins with an examination of the current state of treatment mechanisms research using clinical and social psychological approaches. It then summarizes what is currently understood about the pathophysiology of addiction from a cognitive neuroscience perspective. Finally, it reviews recent efforts to use cognitive neuroscience approaches to understand the neural mechanisms of behavior change in AUD, including studies that use neural functioning to predict relapse and abstinence; studies examining neural mechanisms that operate in current evidence-based behavioral interventions for AUD; as well as research on novel behavioral interventions that are being derived from our emerging understanding of the neural and cognitive mechanisms of behavior change in AUD. The article highlights how the regulation of subcortical regions involved in alcohol incentive motivation by prefrontal cortical regions involved in cognitive control may be a core mechanism that plays a role in these varied forms of behavior change in AUD. We also lay out a multilevel framework for integrating cognitive neuroscience approaches with more traditional methods for examining AUD treatment mechanisms.