Delayed effects of cigarette graphic warning labels on smoking behavior.

Graphic warning labels (GWLs) on cigarette packs are widely employed to communicate smoking-related health risks. Most GWLs elicit high emotional arousal. Our recent study showed lower efficacy of high-arousal GWLs than low-arousal ones during 4 weeks of naturalistic exposure. Here, we conducted a secondary analysis to investigate the delayed effects of GWLs on smoking severity after the end of the 4- week exposure. In 112 adult smokers (56 high-arousal, 56 low-arousal), there was a significant reduction in the number of cigarettes smoked per day (CPD) from immediately post-exposure to 4 weeks post-exposure. The high-arousal and low-arousal groups did not differ in CPD reduction. Our study suggests lasting impact of GWLs on smoking behavior. The finding may be particularly relevant to the high-arousal GWLs, whose efficacy is not as pronounced during direct and continuous exposure.

Hippocampal volume loss in individuals with a history of non-fatal opioid overdose.

Incidence of opioid-related overdoses in the United States has increased dramatically over the past two decades. Despite public emphasis on overdose fatalities, most overdose cases are not fatal. Although there are case reports of amnestic syndromes and acute injury to the hippocampus following non-fatal opioid overdose, the effects of such overdoses on brain structure are poorly understood. Here, we investigated the neuroanatomical correlates of non-fatal opioid overdoses by comparing hippocampal volume in opioid use disorder (OUD) patients who had experienced an opioid overdose (OD; N = 17) with those who had not (NOD; N = 32). Voxel-based morphometry showed lower hippocampal volume in the OD group than in the NOD group, which on post hoc analysis was evident in the left but not the right hippocampus. These findings strengthen the evidence that hippocampal injury is associated with non-fatal opioid overdose, which is hypothesized to underlie overdose-related amnestic syndrome.

Association between body mass index and treatment completion in extended-release naltrexone-treated patients with opioid dependence.

Background: Excessive consumption of opioids is associated with impaired metabolic function including increased body mass index (BMI). Opioid antagonist naltrexone (NTX) is an effective treatment for opioid use disorder (OUD) that has the potential to mitigate such metabolic disturbances. Understanding the relationship between treatment adherence and BMI in NTX-treated OUD patients may provide valuable insights into optimizing clinical outcomes. Methods: Patients with opioid dependence were offered up to three monthly injections of extended-release (XR) NTX. Treatment completers (n = 41) were defined as those who had received all three XR-NTX injections, and non-completers (n = 20) as those missing at least one injection. Logistic regression was performed to examine the association between pre-treatment BMI and treatment completion. Results: BMI was positively associated with treatment completion. This association remained significant after adjusting for potentially confounding variables. Conclusion: Our findings suggest that baseline BMI may serve as a potential predictor of XR-NTX treatment adherence in patients with OUD and could help healthcare providers and policy makers alike in developing strategies to improve retention and tailor interventions for specific patient subgroups.

Effects of current smoking severity on brain gray matter volume in opioid use disorder - a voxel-based morphometry study.

Background: Cigarette smoking (CS) and opioid use disorder (OUD) significantly alter brain structure. Although OUD and cigarette smoking are highly comorbid, most prior neuroimaging research in OUD did not control for smoking severity. Specifically, the combined effect of smoking and OUD on the brain gray matter volume (GMV) remains unknown.Objectives: We used structural magnetic resonance imaging (sMRI) to examine: (1) the GMV differences between OUD and non-OUD individuals with comparable smoking severity; and (2) the differential effect of smoking severity on the brain GMV between individuals with and without OUD.Methods: We performed a secondary analysis of existing sMRI datasets of 116 individuals who smoked cigarettes daily, among whom 60 had OUD (CS-OUD; 37 male, 23 female) and 56 did not (CS; 31 male, 25 female). Brain GMV was estimated by voxel-based morphometry analysis.Results: Compared to the CS group, the CS-OUD group had a higher GMV in the occipital cortex and lower GMV in the prefrontal and temporal cortex, striatum, and pre/postcentral gyrus (whole-brain corrected-p < .05). There was a significant interaction between group and smoking severity on GMV in the medial orbitofrontal cortex (whole-brain corrected-p < .05), such that heavier smoking was associated with lower medial orbitofrontal GMV in the CS-OUD but not CS participants (r=-0.32 vs. 0.12).Conclusions: Our findings suggest a combination of independent and interactive effects of cigarette smoking and OUD on the brain gray matter. Elucidating the neuroanatomical correlates of comorbid opioid and tobacco use may shed the light on the development of novel interventions for affected individuals.

Effects of emotional arousal on the neural impact and behavioral efficacy of cigarette graphic warning labels.

BACKGROUND AND AIMS: Graphic warning labels (GWLs) on cigarette packs have been adopted by many jurisdictions world-wide. In the United States, the introduction of GWLs has been delayed by claims that their high level of negative emotional arousal unnecessarily infringed upon the tobacco manufacturers' free speech. This study aimed to provide experimental data on the contribution of emotional arousal to GWL efficacy. DESIGN: Observational study using long-term naturalistic exposure and functional magnetic resonance imaging. SETTING: Research university in Philadelphia, PA, USA. PARTICIPANTS: A total of 168 adult smokers. MEASUREMENTS: For 4 weeks, participants received cigarettes in packs that carried either high-arousal or low-arousal GWLs (n = 84 versus 84). Smoking behavior, quitting-related cognitions and GWL-induced brain response were measured before and after the 4-week exposure. The amygdala and medial prefrontal cortex served as regions of interest. FINDINGS: Compared with the high-arousal group, the low-arousal group smoked fewer cigarettes [log10 -transformed, 1.076 versus 1.019; difference = 0.056, 95% confidence interval (CI) = 0.027, 0.085, χ2 (1)  = 14.21, P < 0.001] and showed stronger intention to quit (2.527 versus 2.810; difference = -0.283, 95% CI = -0.468, -0.098, χ2 (1) = 8.921, P = 0.007) and endorsement of the GWLs' textual component (4.805 versus 5.503; difference = -0.698, 95% CI = -1.016, -0.380, χ2 (1) = 18.47, P < 0.001). High-arousal GWLs induced greater amygdala response than low-arousal GWLs (0.157 versus 0.052; difference = 0.105, 95% CI = 0.049, 0.161, χ2 (1) = 23.52, P < 0.001), although the response to high-arousal GWLs declined over time (slope = -0.087 versus 0.016; difference = -0.103, 95% CI = -0.198, -0.009, χ2 (1) = 6.370, P = 0.046). Greater baseline amygdala response was associated with more smoking at 4 weeks in the high-arousal group, but less smoking in the low-arousal group (slope = 0.179 versus -0.122; difference = 0.287, 95% CI = 0.076, 0.498, χ2 (1) = 7.086, P = 0.008). Medial prefrontal response did not differ significantly between groups. CONCLUSIONS: High-arousal cigarette graphic warning labels (GWLs) appear to be less efficacious than low-arousal GWLs. The high emotional reaction that high-arousal GWLs elicit wanes over time. Baseline amygdala response negatively predicts efficacy of high-arousal GWLs and positively predicts efficacy of low-arousal GWLs. High emotional arousal may not be required for sustained GWL efficacy.

Addicted to green: priming effect of menthol cigarette packaging on brain response to smoking cues.

INTRODUCTION: Mentholated tobacco cigarettes are believed to be more addictive than non-menthol ones. Packaging of most menthol cigarette brands includes distinctive green hues, which may act as conditioned stimuli (ie, cues) and promote menthol smoking. To examine the cue properties of menthol cigarette packaging, we used a priming paradigm to assess the effect of packaging on the neural substrates of smoking cue reactivity. We hypothesised that menthol packaging will exert a specific priming effect potentiating smoking cue reactivity in menthol compared with non-menthol smokers. METHODS: Forty-two menthol and 33 non-menthol smokers underwent functional MRI while viewing smoking and neutral cues. The cues were preceded (ie, primed) by briefly presented images of menthol or non-menthol cigarette packages. Participants reported craving for cigarettes in response to each cue. RESULTS: Menthol packaging induced greater frontostriatal and occipital smoking cue reactivity in menthol smokers than in non-menthol smokers. Menthol packaging also enhanced the mediation by neural activity of the relationship between cue exposure and cigarette craving in menthol but not non-menthol smokers. Dynamic causal modelling showed stronger frontostriatal-occipital connectivity in response to menthol packaging in menthol compared with non-menthol smokers. The effects of non-menthol packaging did not differ between categories of smokers. CONCLUSIONS: Our findings demonstrate heightened motivational and perceptual salience of the green-hued menthol cigarette packaging that may exacerbate menthol smokers' susceptibility to smoking cues. These effects could contribute to the greater addiction severity among menthol smokers and could be considered in the development of science-based regulation and legal review of tobacco product marketing practices.

Baseline- and treatment-associated pain in the X:BOT comparative effectiveness study of extended-release naltrexone versus buprenorphine-naloxone for OUD.

Chronic pain is highly prevalent among patients with opioid use disorder (OUD). However, little is known about how pharmacological treatments for OUD, for example, extended-release naltrexone (XR-NTX) and buprenorphine-naloxone (BUP-NX), affect pain. To begin addressing this question, we performed a secondary analysis of pain data on a large prospective 24-week, open-label, randomized-controlled comparative effectiveness trial of XR-NTX versus BUP-NX (X:BOT trial). Participants' pain status was measured by the EuroQol (EQ-5D). Based on their responses to the pain question at baseline, participants were dichotomized into "Pain" versus "No Pain" categories. Participant's pain status was evaluated every 4 weeks. A mixed effects longitudinal logistic regression model was fitted to examine the differential effect of XR-NTX versus BUP-NX on pain, modelling pain at all available follow-up assessments, adjusted for age, sex, and baseline pain. A total of 474 individuals who were successfully inducted onto their assigned medications were included in this analysis. Among participants endorsing pain at baseline, substantial reductions in pain were observed over the course of the study in both treatment groups. Howecver reduction in pain was slightly greater in the group treated with XR-NTX than the one treated with BUP-NX (OR = 1.60 [95% CI: 1.07-2.40], P = 0.023). Future research using instruments and design specifically focused on pain could extend the present observations and evaluate their clinical significance.

Multivariate pattern analysis links drug use severity to distributed cortical hypoactivity during emotional inhibitory control in opioid use disorder.

Opioid use disorder (OUD) is characterized by emotional and cognitive impairements that are associated with poor treatment outcomes. The present study investigated the neural mechanism underlying emotion evaluation and inhibitory control using an affective go/no-go (AGN) task and its association with drug use severity and craving in patients with OUD. Twenty-six recently detoxified patients with OUD underwent functional magnetic resonance imaging (fMRI) while performing the AGN task that required response to frequently presented appetitive stimuli ("go") and inhibition of response to infrequently presented aversive stimuli ("no-go"). The fMRI session was immediately followed by an injection of extended-release opioid antagonist naltrexone (XR-NTX). Participants' opioid craving was assessed immediately before fMRI and 10 ± 2 days after XR-NTX injection. Multivariate pattern analysis (MVPA) showed that drug use severity was associated with distributed brain hypoactivity in response to aversive no-go stimuli, with particularly large negative contributions from the cognitive control and dorsal attention brain networks. While drug use severity and its associated MVPA brain response pattern were both correlated with opioid craving at baseline, only the brain response pattern predicted craving during XR-NTX treatment. Our findings point to widespread functional hypoactivity in the brain networks underlying emotional inhibitory control in OUD. Such a distributed pattern is consistent with the multifaceted nature of OUD, which affects multiple brain networks. It also highlights the utility of the multivariate approach in uncovering large-scale cortical substrates associated with clinical severity in complex psychiatric disorders and in predicting treatment response.

Sustained brain response to repeated drug cues is associated with poor drug-use outcomes.

A threefold increase in fatal cocaine overdoses during the past decade highlights the critical lack of medications for cocaine use disorders. The brain response to drug cues can predict future drug use; however, results have been mixed. We present preliminary evidence that a sustained response to repeated cocaine cues within a single task is a significant predictor of drug-use outcomes. Seventy-three cocaine inpatients were administered a passive-viewing fMRI task, featuring 500 ms novel evocative (cocaine, sexual, aversive) and neutral comparator cues in the first half (Half1), which were then repeated in the second half (Half2). After the baseline scan, patients received eight outpatient treatment weeks with twice-weekly drug screens. Drug-use outcome groups were empirically defined based on cocaine-positive or missing urines averaged across the outpatient phase: GOOD (<40%), POOR (>85%), and Intermediate (INT, between 40% and 85%) outcomes. Differences of response to initial (Half1) and repeated (Half2) cues in a priori (cue-reactive) regions were tested between outcome groups (3 [Group] × 2 [Halves] ANOVA). An interaction was found in the brain response to drug (but not sex or aversive) cues, with a significant difference between the GOOD and POOR outcome groups in Half2, driven by a significant decrease in brain response by the GOOD outcome group and a sustained brain response by the POOR outcome group, to repeated cocaine cues. The brain response to repeated drug cues may be a useful predictor of future drug use, encouraging future intervention studies to restore a "healthy" (decreasing) response to the repeated presentation of drug cues.

The role of withdrawal in mesocorticolimbic drug cue reactivity in opioid use disorder.

Opioid use disorder (OUD) is characterized by heightened cognitive, physiological, and neural responses to opioid-related cues that are mediated by mesocorticolimbic brain pathways. Craving and withdrawal are key symptoms of addiction that persist during physiological abstinence. The present study evaluated the relationship between the brain response to drug cues in OUD and baseline levels of craving and withdrawal. We used functional magnetic resonance imaging (fMRI) to examine brain responses to opioid-related pictures and control pictures in 29 OUD patients. Baseline measures of drug use severity, opioid craving, and withdrawal symptoms were assessed prior to cue exposure and correlated with subsequent brain responses to drug cues. Mediation analysis was conducted to test the indirect effect of drug use severity on brain cue reactivity through craving and withdrawal symptoms. We found that baseline drug use severity and opioid withdrawal symptoms, but not craving, were positively associated with the neural response to drug cues in the nucleus accumbens, orbitofrontal cortex, and amygdala. Withdrawal, but not craving, mediated the effect of drug use severity on the nucleus accumbens' response to drug cues. We did not find similar effects for the neural responses to stimuli unrelated to drugs. Our findings emphasize the central role of withdrawal symptoms as the mediator between the clinical severity of OUD and the brain correlates of sensitization to opioid-related cues. They suggest that in OUD, baseline withdrawal symptoms signal a high vulnerability to drug cues.

Reduced cigarette smoking during injectable extended-release naltrexone treatment for opioid use disorder.

BACKGROUND: The prevalence of tobacco cigarette smoking in the US has declined to approximately 15%, yet, it remains over 90% among individuals with opioid use disorder regardless of whether they are currently using opioids illicitly or as opioid substitution therapy. This disparity raises the question of whether opioids facilitate smoking among individuals with opioid use disorder and whether opioid antagonists may reduce it. OBJECTIVES: Determine whether injectable extended-release naltrexone (XR-NTX) treatment of opioid use disorder patients is associated with a spontaneous smoking reduction. We hypothesized that treatment with XR-NTX for would lead to a reduction in smoking in tobacco cigarette smokers with opioid use disorder. METHODS: We analyzed data from 64 tobacco cigarette smokers (38% female) with opioid use disorder who were induced on XR-NTX for prevention of relapse to opioids. The number of cigarettes smoked per day and opioid-related craving and withdrawal were assessed at baseline and during treatment. RESULTS: Smoking was reduced from 14.4 ± 1.0 to 9.8 ± 1.0(p < 0.001) cigarettes per day after one month and 8.6 ± 1.1 cigarettes per day after two months of treatment. Daily cigarette consumption was positively correlated with the pre-treatment frequency of opioid use and opioid-related craving during the XR-NTX treatment. CONCLUSIONS: XR-NTX treatment in smokers with opioid use disorder was associated with a 29% decline in daily cigarette consumption. Together with prior evidence of increased smoking during opioid agonist therapy, our finding suggests a pharmacodynamic interaction between nicotine and opioid systems that could influence treatment choices in this population. Our findings merit confirmation in a prospective controlled study. (NCT02324725 and NCT01587196).

Connectivity between visual and auditory cortices mediates the influence of argument strength on the effectiveness of smoking-cessation videos among smokers low in sensation seeking.

PURPOSE: Argument strength (AS) is a validated measure of persuasiveness that has been identified as one of the key variables determining the effectiveness of video ads. Smoking-cessation videos with high AS are more effective at reducing smoking behavior than videos with low AS. The neural processes that mediate the effects of AS on subsequent smoking have not been identified. In the present study, we tested whether the efficacy of high-AS smoking-cessation videos is determined by the level of integration of visual and auditory (ie, multisensory) processes. In addition, we tested differences in sensation seeking, which is repeatedly associated with smokers' sensitivity to cessation interventions. PATIENTS AND METHODS: Using functional magnetic resonance imaging (fMRI), we recorded the brain response of 66 smokers randomly assigned to view either 16 high-AS or 16 low-AS smoking-cessation videos. Multisensory processing was assessed by the functional connectivity between brain regions that encoded visual and auditory information in the videos. Smoking behavior was indexed by the urine level of cotinine, a nicotine metabolite, immediately before and approximately 30 days after the fMRI session. RESULTS: We found a significant moderated mediation effect, such that the connectivity between visual and auditory cortices mediated the effect of AS on subsequent smoking, but only for smokers lower in sensation seeking. The prediction performance of the model was confirmed by leave-one-out cross-validation. CONCLUSION: Our study suggests that audiovisual integration underlies the greater efficacy of high- vs low-AS smoking-cessation videos for individuals lower in sensation seeking. High-sensation-seeking smokers may be responsive to other characteristics of smoking-cessation videos.

Behavioral and Accumbal Responses During an Affective Go/No-Go Task Predict Adherence to Injectable Naltrexone Treatment in Opioid Use Disorder.

Adherence is a major factor in the effectiveness of the injectable extended-release naltrexone as a relapse prevention treatment in opioid use disorder. We examined the value of a variant of the Go/No-go paradigm in predicting extended-release naltrexone adherence in 27 detoxified opioid use disorder patients who were offered up to 3 monthly extended-release naltrexone injections. Before extended-release naltrexone, participants performed a Go/No-go task that comprised positively valenced Go trials and negatively valenced No-go trials during a functional magnetic resonance imaging scan. Errors of commission and neural responses to the No-go vs Go trials were independent variables. Adherence, operationalized as the completion of all 3 extended-release naltrexone injections, was the outcome variable. Fewer errors of commission and greater left accumbal response during the No-go vs Go trials predicted better adherence. These findings support the clinical potential of the behavioral and neurophysiological correlates of response inhibition in the prediction of extended-release naltrexone treatment outcomes in opioid use disorder.

Emotional salience of the image component facilitates recall of the text of cigarette warning labels.

Background: Graphic warning labels (GWLs) on cigarette packages, that combine textual warnings with emotionally salient images depicting the adverse health consequences of smoking, have been adopted in most European countries. In the US, the courts deemed the evidence justifying the inclusion of emotionally salient images in GWLs insufficient and put the implementation on hold. We conducted a controlled experimental study examining the effect of emotional salience of GWL's images on the recall of their text component. Methods: Seventy-three non-treatment-seeking daily smokers received cigarette packs carrying GWLs for a period of 4 weeks. Participants were randomly assigned to receive packs with GWLs previously rated as eliciting high or low level of emotional reaction (ER). The two conditions differed in respect to images but used the same textual warning statements. Participants' recognition of GWL images and statements were tested separately at baseline and again after the 4-week repetitive exposure. Results: Textual warning statements were recognized more accurately when paired with high ER images than when paired with low ER images, both at baseline and after daily exposure to GWLs over a 4-week period. Conclusion: The results suggest that emotional salience of GWLs facilitates cognitive processing of the textual warnings, resulting in better remembering of the information about the health hazards of smoking. Thus, high emotional salience of the pictorial component of GWLs is essential for their overall effectiveness.

Multi-View Cluster Analysis with Incomplete Data to Understand Treatment Effects.

Multi-view cluster analysis, as a popular granular computing method, aims to partition sample subjects into consistent clusters across different views in which the subjects are characterized. Frequently, data entries can be missing from some of the views. The latest multi-view co-clustering methods cannot effectively deal with incomplete data, especially when there are mixed patterns of missing values. We propose an enhanced formulation for a family of multi-view co-clustering methods to cope with the missing data problem by introducing an indicator matrix whose elements indicate which data entries are observed and assessing cluster validity only on observed entries. In comparison with the simple strategy of removing subjects with missing values, our approach can use all available data in cluster analysis. In comparison with common methods that impute missing data in order to use regular multi-view analytics, our approach is less sensitive to imputation uncertainty. In comparison with other state-of-the-art multi-view incomplete clustering methods, our approach is sensible in the cases of missing any value in a view or missing the entire view, the most common scenario in practice. We first validated the proposed strategy in simulations, and then applied it to a treatment study of heroin dependence which would have been impossible with previous methods due to a number of missing-data patterns. Patients in a treatment study were naturally assessed in different feature spaces such as in the pre-, during-and post-treatment time windows. Our algorithm was able to identify subgroups where patients in each group showed similarities in all of the three time windows, thus leading to the recognition of pre-treatment (baseline) features predictive of post-treatment outcomes.

Reward and aversion processing in patients with post-traumatic stress disorder: functional neuroimaging with visual and thermal stimuli.

In patients with post-traumatic stress disorder (PTSD), a decrease in the brain reward function was reported in behavioral- and in neuroimaging studies. While pathophysiological mechanisms underlying this response are unclear, there are several lines of evidence suggesting over-recruitment of the brain reward regions by aversive stimuli rendering them unavailable to respond to reward-related content. The purpose of this study was to juxtapose brain responses to functional neuroimaging probes that reliably produce rewarding and aversive experiences in PTSD subjects and in healthy controls. The stimuli used were pleasant, aversive and neutral images selected from the International Affective Picture System (IAPS) along with pain-inducing heat applied to the dorsum of the left hand; all were administered during 3 T functional magnetic resonance imaging. Analyses of IAPS responses for the pleasant images revealed significantly decreased subjective ratings and brain activations in PTSD subjects that included striatum and medial prefrontal-, parietal- and temporal cortices. For the aversive images, decreased activations were observed in the amygdala and in the thalamus. PTSD and healthy subjects provided similar subjective ratings of thermal sensory thresholds and each of the temperatures. When 46 °C (hot) and 42 °C (neutral) temperatures were contrasted, voxelwise between-group comparison revealed greater activations in the striatum, amygdala, hippocampus and medial prefrontal cortex in the PTSD subjects. These latter findings were for the most part mirrored by the 44 vs. 42 °C contrast. Our data suggest different brain alterations patterns in PTSD, namely relatively diminished corticolimbic response to pleasant and aversive psychosocial stimuli in the face of exaggerated response to heat-related pain. The present findings support the hypothesis that brain sensitization to pain in PTSD may interfere with the processing of psychosocial stimuli whether they are of rewarding or aversive valence.

Effects of extended-release naltrexone on the brain response to drug-related stimuli in patients with opioid use disorder.

BACKGROUND: Heightened response to drug-related cues is a hallmark of addiction. Extended-release naltrexone (XR-NTX) is a US Food and Drug Administration-approved pharmacotherapy for relapse prevention in patients with opioid use disorder (OUD). In these patients, XR-NTX has been shown to reduce brain responses to opioid-related visual stimuli. To assess the biomarker potential of this phenomenon, it is necessary to determine whether this effect is limited to opioid-related stimuli and whether it is associated with key OUD symptoms. METHODS: Using functional MRI (fMRI), we measured the brain responses to opioid-related and control (i.e., sexual and aversive) images in detoxified patients with OUD before, during and after XR-NTX treatment. Craving and withdrawal severity were evaluated using clinician- and self-administered instruments during each session. RESULTS: We included 24 patients with OUD in our analysis. During XR-NTX treatment, we found reduced responses to opioid-related stimuli in the nucleus accumbens (NAcc) and medial orbitofrontal cortex (mOFC). The reduction in mOFC response was specific to the opioid-related stimuli. The reduced NAcc and mOFC opioid cue reactivity was correlated with reduction in clinician-assessed and self-reported withdrawal symptoms, respectively. LIMITATIONS: The study was not placebo-controlled owing to ethical, safety and feasibility concerns. CONCLUSION: Extended-release naltrexone reduces the NAcc and mOFC cue reactivity in patients with OUD. This effect is specific to opioid-related stimuli in the mOFC only. The reduction in neural response to opioid-related stimuli is more robust in patients with greater decline in withdrawal severity. Our results support the clinical utility of mesocorticolimbic cue reactivity in monitoring the XR-NTX treatment outcomes and highlight the link between opioid withdrawal symptomatology and neural opioid cue reactivity.

Effects of extended-release naltrexone on the brain response to drug-related stimuli in patients with opioid use disorder.

BACKGROUND: Heightened response to drug-related cues is a hallmark of addiction. Extended-release naltrexone (XR-NTX) is a US Food and Drug Administration-approved pharmacotherapy for relapse prevention in patients with opioid use disorder (OUD). In these patients, XR-NTX has been shown to reduce brain responses to opioid-related visual stimuli. To assess the biomarker potential of this phenomenon, it is necessary to determine whether this effect is limited to opioid-related stimuli and whether it is associated with key OUD symptoms. METHODS: Using functional MRI (fMRI), we measured the brain responses to opioid-related and control (i.e., sexual and aversive) images in detoxified patients with OUD before, during and after XR-NTX treatment. Craving and withdrawal severity were evaluated using clinician- and self-administered instruments during each session. RESULTS: We included 24 patients with OUD in our analysis. During XR-NTX treatment, we found reduced responses to opioid-related stimuli in the nucleus accumbens (NAcc) and medial orbitofrontal cortex (mOFC). The reduction in mOFC response was specific to the opioid-related stimuli. The reduced NAcc and mOFC opioid cue reactivity was correlated with reduction in clinician-assessed and self-reported withdrawal symptoms, respectively. LIMITATIONS: The study was not placebo-controlled owing to ethical, safety and feasibility concerns. CONCLUSION: Extended-release naltrexone reduces the NAcc and mOFC cue reactivity in patients with OUD. This effect is specific to opioid-related stimuli in the mOFC only. The reduction in neural response to opioid-related stimuli is more robust in patients with greater decline in withdrawal severity. Our results support the clinical utility of mesocorticolimbic cue reactivity in monitoring the XR-NTX treatment outcomes and highlight the link between opioid withdrawal symptomatology and neural opioid cue reactivity.