Imaging neuroinflammation in individuals with substance use disorders.

Increasing evidence suggests a role of neuroinflammation in substance use disorders (SUDs). This Review presents findings from neuroimaging studies assessing brain markers of inflammation in vivo in individuals with SUDs. Most studies investigated the translocator protein 18 kDa (TSPO) using PET; neuroimmune markers myo-inositol, choline-containing compounds, and N-acetyl aspartate using magnetic resonance spectroscopy; and fractional anisotropy using MRI. Study findings have contributed to a greater understanding of neuroimmune function in the pathophysiology of SUDs, including its temporal dynamics (i.e., acute versus chronic substance use) and new targets for SUD treatment.

Blood pressure response to extended-release naltrexone in heroin and prescription opioid users and its implications for cardiovascular morbidity.

BACKGROUND: Consuming opioid agonists is a risk factor for cardiovascular disease particularly in intravenous heroin users. The monthly injectable extended-release opioid antagonist, naltrexone (XR-NTX) is an effective treatment for opioid use disorder. The impact of opioid receptor blockade through XR-NTX on blood pressure, a critical risk factor for cardiovascular morbidity, has not yet been characterized. METHODS: The study evaluated the change in blood pressure during XR-NTX treatment among 14 patients who predominately used intravenous heroin and 24 patients who used prescription oral opioids, all with opioid use disorder. Blood pressure was measured in each patient immediately before the first XR-NTX injection and ∼two weeks after the first injection. The change in diastolic and systolic pressure was compared between the heroin users and the prescription opioids users using analysis of variance. RESULTS: XR-NTX treatment was associated with significant decreases in diastolic blood pressure in the heroin group, but not in the prescription opioids group. Systolic blood pressure values in the heroin users showed a decline at trend level only. CONCLUSIONS: Further research is warranted to replicate our findings and to determine whether XR-NTX effect is relatively specific to blood pressure or generalizes to other components of metabolic syndrome. Distinguishing between heroin and prescription opioid users could shed light on the unique clinical and pharmacological profiles of opioid drugs, particularly regarding their cardiovascular safety. This information can be useful in developing personalized therapeutic strategies based on the route of opioid administration.

Ketone Supplementation Dampens Subjective and Objective Responses to Alcohol: Evidence From a Preclinical Rat Study and a Randomized, Cross-Over Trial in Healthy Volunteers.

BACKGROUND: Previous preclinical and human studies have shown that a high-fat ketogenic diet and ketone supplements (KS) are efficacious in reducing alcohol craving, alcohol consumption, and signs of alcohol withdrawal. However, the effects of KS on alcohol sensitivity are unknown. METHODS: In this single-blind, cross-over study, 10 healthy participants (3 females) were administered a single, oral dose of a KS (25 g of ketones from D-ß-hydroxybutyric acid and R-1,3-butanediol) or placebo 30 minutes before an oral alcohol dose (0.25 g/kg for women; 0.31 g/kg for men). Assessments of breath alcohol concentration and blood alcohol levels (BAL) and responses on the Drug Effect Questionnaire were repeatedly obtained over 180 minutes after alcohol consumption. In a parallel preclinical study, 8 Wistar rats (4 females) received an oral gavage of KS (0.42 g ketones/kg), water, or the sweetener allulose (0.58 g/kg) followed 15 minutes later by an oral alcohol dose (0.8 g/kg). BAL was monitored for 240 minutes after alcohol exposure. RESULTS: In humans, the intake of KS before alcohol significantly blunted breath alcohol concentration and BAL, reduced ratings of alcohol liking and wanting more, and increased disliking for alcohol. In rats, KS reduced BAL more than either allulose or water. CONCLUSION: KS altered physiological and subjective responses to alcohol in both humans and rats, and the effects were likely not mediated by the sweetener allulose present in the KS drink. Therefore, KS could potentially reduce the intoxicating effects of alcohol.

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.

Vaping and smoking cue reactivity in young adult electronic cigarette users who have never smoked combustible cigarettes: A functional neuroimaging study.

Introduction: The rapid growth in the use of electronic cigarettes (e-cigarettes) among young adults who have never smoked combustible cigarettes is concerning, as it raises the potential for chronic vaping and nicotine addiction. A key characteristic of drug addiction is the elevated neural response to conditioned drug-related cues (i.e., cue reactivity). Generalized reactivity to both vaping and smoking cues may signify an increased risk for smoking initiation in non- smoking vapers. In this study, we used functional magnetic resonance imaging (fMRI) to evaluate brain responses to vaping and smoking cues in young adult never-smoking vapers. Methods: Sixty-six young adult never-smoking vapers underwent functional MRI while viewing visual cues pertaining to vaping, smoking, and nicotine-unrelated unconditioned reward (i.e., food). A priori region-of-interest analysis combined with exploratory whole-brain analysis was performed to characterize neural reactivity to vaping and smoking cues in comparison to food cues. Results: The medial prefrontal cortex and the posterior cingulate cortex, regions that play a key role in drug cue reactivity, showed significantly increased neural response to vaping cues compared to food cues. The posterior cingulate cortex additionally showed increased neural responses to smoking cues compared to food cues. Conclusions: Despite never having smoked combustible cigarettes, young adult vapers exhibited heightened neural susceptibility to both vaping and smoking cues within brain systems associated with cue reactivity. The findings shed light on the mechanisms underlying nicotine addiction and smoking initiation risk in this critical population and may contribute to the development of science-based interventions and regulatory measures in the future. IMPLICATIONS: The escalating vaping prevalence among US never-smoking young adults is alarming, due to its potential ramifications for nicotine addiction development. Nicotine addiction is characterized by elevated neural response to conditioned nicotine-related cues. Using functional neuroimaging, we showed that young adult non-smoking vapers exhibited heightened neural susceptibility to both vaping and smoking cues within brain systems previously associated with cue reactivity. Such cross-reactivity to both types of nicotine cues may serve as the mechanism underlying nicotine addiction and smoking initiation risk in this population. Our findings may contribute to the development of science-based interventions and regulatory measures addressing the vaping epidemic.

Metabolic profiles associated with opioid use and opioid use disorder: a narrative review of the literature.

Purpose of Review: Opioid use disorder (OUD) is a chronic, relapsing condition that is epidemic in the USA. OUD is associated with serious adverse consequences, including higher incarceration rates, impaired medical and mental health, and overdose-related fatalities. Several medications with demonstrated clinical efficacy in reducing opioid use are approved to treat OUD. However, there is evidence that medications for OUD cause metabolic impairments, which raises concerns over the long-term metabolic health of individuals recovering from OUD. Here, we summarize the scientific literature on the metabolic effects of the use of opioids, including medications for treating OUD. Recent Findings: Our findings showed lower body weight and adiposity, and better lipid profiles in individuals with OUD. In individuals with diabetes mellitus, opioid use was associated with lower blood glucose levels. In contrast, among individuals without underlying metabolic conditions, opioids promoted insulin resistance. Treatment of OUD patients with the agonists methadone or buprenorphine caused weight gain, increased liking and intake of sugar, and impaired lipid profile and glucose metabolism, whereas treatment with the antagonist naltrexone demonstrated evidence for reduced sweet preferences. Summary: Our findings highlighted a gap in knowledge regarding the safety of medications for OUD. Further research is needed to determine how best to reduce the risk of metabolic disorder in the treatment of OUD with opioid agonists versus antagonists.

Ketone supplementation dampens subjective and objective responses to alcohol in rats and humans.

Previous preclinical and human studies have shown that high-fat ketogenic diet and ketone supplements (KS) are efficacious in reducing alcohol craving, alcohol consumption, and signs of alcohol withdrawal. However, the effects of KS on alcohol sensitivity are unknown. In this single-blind, cross-over study, 10 healthy participants (3 females) were administered a single, oral dose of a KS (25 g of ketones from D-ß-hydroxybutyric acid and R-1,3-butanediol) or placebo 30 min prior to an oral alcohol dose (0.25 g/kg for women; 0.31 g/kg for men). Assessments of breath alcohol concentration (BrAC) and blood alcohol levels (BAL) and responses on the Drug Effect Questionnaire were repeatedly obtained over 180 min after alcohol consumption. In a parallel preclinical study, 8 Wistar rats (4 females) received an oral gavage of KS (0.42 g ketones/kg), water, or the sweetener allulose (0.58 g/kg) followed 15 min later by an oral alcohol dose (0.8 g/kg). BAL were monitored for 240 min after alcohol exposure. In humans, the intake of KS prior to alcohol significantly blunted BrAC and BAL, reduced ratings of alcohol liking and wanting, and increased disliking for alcohol. In rats, KS reduced BAL more than either allulose or water. In conclusion, KS altered physiological and subjective responses to alcohol in both humans and rats and the effects were likely not mediated by the sweetener allulose present in the KS drink. Therefore, KS could potentially reduce the intoxicating and rewarding effects of alcohol and thus be a novel intervention for treating alcohol use disorder.

Pharmacokinetic effects of a single-dose nutritional ketone ester supplement on brain ketone and glucose metabolism in alcohol use disorder - a pilot study.

Introduction: Acute alcohol intake decreases brain glucose metabolism and increases brain uptake of acetate, a metabolite of alcohol. Individuals with alcohol use disorder (AUD) show elevated brain acetate metabolism at the expense of glucose, a shift in energy utilization that persists beyond acute intoxication. We recently reported that nutritional ketosis and administration of ketone bodies as an alternative energy source to glucose reduce alcohol withdrawal severity and alcohol craving in AUD. However, the regional effects of nutritional ketosis on brain ketone (beta-hydroxybutyrate [BHB]) and glucose metabolism have not been studied in AUD. Methods: Five participants with AUD underwent two magnetic resonance imaging (MRI) sessions and 4 participants with AUD underwent two positron emission tomography (PET) sessions with 18 F-fluorodeoxyglucose. All participants completed one session without KE intervention and one session during which they consumed 395 mg/kg (R) -3-hydroxybutyl (R) -3-hydroxybutyrate Ketone Ester (KE) intervention (TdeltaS Global Inc.) before the scan. The order of the sessions was randomized. For the PET cohort, blood glucose and ketone levels were assessed and voxel-wise maps of the cerebral metabolic rate of glucose (CMRglc) were computed at each session. For the MRI cohort, brain anterior cingulate BHB levels were assessed using magnetic resonance spectroscopy. Results: A single dose of KE elevated blood BHB and anterior cingulate BHB levels compared to baseline. Moreover, blood glucose levels were lower with KE than baseline, and whole-brain CMRglc decreased by 17%. The largest KE-induced CMRglc reductions were in the frontal, occipital, cortex, and anterior cingulate cortices. Conclusion: These findings provide preliminary evidence that KE administration elevates ketone and reduces brain glucose metabolism in humans, consistent with a shift from glucose to ketones as a brain energy source. Average reductions in CMRglc of 17% are similar to global average reductions documented with administration of 0.25-0.5 g/kg of alcohol. Documenting the clinical and neurometabolic effects of nutritional ketosis will yield fundamental knowledge as to its potential beneficial effects as a treatment for AUD and its underlying neural mechanisms.

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.

Neural habituation during acute stress signals a blunted endocrine response and poor resilience.

BACKGROUND: A blunted hypothalamic-pituitary-adrenal (HPA) axis response to acute stress is associated with psychiatric symptoms. Although the prefrontal cortex and limbic areas are important regulators of the HPA axis, whether the neural habituation of these regions during stress signals both blunted HPA axis responses and psychiatric symptoms remains unclear. In this study, neural habituation during acute stress and its associations with the stress cortisol response, resilience, and depression were evaluated. METHODS: Seventy-seven participants (17-22 years old, 37 women) were recruited for a ScanSTRESS brain imaging study, and the activation changes between the first and last stress blocks were used as the neural habituation index. Meanwhile, participants' salivary cortisol during test was collected. Individual-level resilience and depression were measured using questionnaires. Correlation and moderation analyses were conducted to investigate the association between neural habituation and endocrine data and mental symptoms. Validated analyses were conducted using a Montreal Image Stress Test dataset in another independent sample (48 participants; 17-22 years old, 24 women). RESULTS: Neural habituation of the prefrontal cortex and limbic area was negatively correlated with cortisol responses in both datasets. In the ScanSTRESS paradigm, neural habituation was both positively correlated with depression and negatively correlated with resilience. Moreover, resilience moderated the relationship between neural habituation in the ventromedial prefrontal cortex and cortisol response. CONCLUSIONS: This study suggested that neural habituation of the prefrontal cortex and limbic area could reflect motivation dysregulation during repeated failures and negative feedback, which might further lead to maladaptive mental states.

Peripheral and Central Iron Measures in Alcohol Use Disorder and Aging: A Quantitative Susceptibility Mapping Pilot Study.

Chronic excessive alcohol use has neurotoxic effects, which may contribute to cognitive decline and the risk of early-onset dementia. Elevated peripheral iron levels have been reported in individuals with alcohol use disorder (AUD), but its association with brain iron loading has not been explored. We evaluated whether (1) serum and brain iron loading are higher in individuals with AUD than non-dependent healthy controls and (2) serum and brain iron loading increase with age. A fasting serum iron panel was obtained and a magnetic resonance imaging scan with quantitative susceptibility mapping (QSM) was used to quantify brain iron concentrations. Although serum ferritin levels were higher in the AUD group than in controls, whole-brain iron susceptibility did not differ between groups. Voxel-wise QSM analyses revealed higher susceptibility in a cluster in the left globus pallidus in individuals with AUD than controls. Whole-brain iron increased with age and voxel-wise QSM indicated higher susceptibility with age in various brain areas including the basal ganglia. This is the first study to analyze both serum and brain iron loading in individuals with AUD. Larger studies are needed to examine the effects of alcohol use on iron loading and its associations with alcohol use severity, structural and functional brain changes, and alcohol-induced cognitive impairments.

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.

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.

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.

Brain glutamate and sleep efficiency associations following a ketogenic diet intervention in individuals with Alcohol Use Disorder.

Background: We previously showed that ketogenic diet (KD) was effective in curbing alcohol withdrawal and craving in individuals with alcohol use disorder (AUD). We hypothesized that the clinical benefits were due to improvements in sleep. To test this, we performed a secondary analysis on the KD trial data to (1) examine the effects of KD on total sleep time (TST) and sleep quality and (2) investigate the association between KD-induced alterations in cingulate glutamate concentration and changes in TST and sleep quality. Methods: AUD individuals undergoing alcohol detoxification were randomized to receive KD (n=19) or standard American diet (SA; n=14) for three weeks. TST was measured weekly by self-report, GENEActive sleep accelerometer, and X4 Sleep Profiler ambulatory device. Sleep quality was assessed using subjectively ratings of sleep depth and restedness and Sleep Profiler (Sleep Efficiency [%]). Weekly 1H magnetic resonance spectroscopy scans measured cingulate glutamate levels. Results: TST was lower in KD than SA and increased with effect of time. Sleep depth, restedness, and Sleep Efficiency improved with time, but exhibited no effect of diet. In KD and SA combined, week 1 cingulate glutamate levels correlated positively with Sleep Efficiency, but not with TST. Conclusions: Although cingulate glutamate levels correlated positively with Sleep Efficiency in week 1, KD-induced glutamate elevation did not produce significant sleep improvements. Rather, KD was associated with lower TST than SA. Given the well-established associations between sleep and alcohol relapse, longer follow up assessment of KD's impact on sleep in AUD is warranted.

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.

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).