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RationaleProinflammatory processes have been implicated in alcohol addiction, craving, and relapse, while studies in experimental animals have suggested that activation of peroxisome proliferator-activated receptor gamma (PPARγ) inhibits proinflammatory signaling. Accordingly, it is hypothesized that medications with PPARγ activity may have therapeutic potential in alcohol dependence.ObjectivesWe conducted a double-blind, placebo-controlled mechanistic proof of principle study in alcohol-dependent inpatients to investigate the effect of pioglitazone on alcohol craving.MethodsParticipants were treated for withdrawal, if needed, and then randomized to pioglitazone (target dose 45 mg/day) or placebo. Once at target dose, they completed two experimental manipulations: guided imagery, which used personalized auditory scripts to induce alcohol cravings, and a low-dose challenge with i.v. lipopolysaccharide (LPS; 0.8 ng/kg) or placebo, on two separate sessions, in counterbalanced order. Behavioral and endocrine responses as well as CSF levels of proinflammatory cytokines were evaluated.ResultsThe study was prematurely terminated after randomization of 16 subjects, following an independent review that established a high risk of myopathy in the active treatment group. Analysis of those who completed the study indicated that pioglitazone was associated with elevated, rather than suppressed alcohol cravings in response to alcohol-associated stimuli. LPS did not induce cravings for alcohol and thus did not lend itself to evaluating pioglitazone effects; however, pioglitazone increased the neuroendocrine stress response to LPS. CSF levels of IL-6, TNF-α, or MCP-1 were unaffected by pioglitazone treatment.ConclusionsBoth safety and efficacy biomarker data suggest that pioglitazone lacks potential as a medication for the treatment of alcohol dependence.Clinical trial registrationNCT01631630

Preclinical research with rodents suggests that the L-type calcium channel blocker isradipine can enhance long-term extinction of conditioned place preference for addictive substances when it is administered in conjunction with extinction training. Although isradipine alone, which is FDA-approved for hypertension, has not shown a direct effect on craving in human drug users, its potential to augment behavioral treatments designed to reduce craving remains unknown. We conducted a triple-blind, randomized placebo-controlled pilot clinical trial of isradipine combined with a novel virtual reality cue exposure therapy (VR-CET) approach with multimodal cues that targeted craving. After 24 hours of abstinence, 78 adults with an ongoing history of daily cigarette use received isradipine (n = 40) or placebo (n = 38) and reported craving levels after each of 10 trials of VR-CET. Consistent with pre-registered hypotheses, the isradipine group had significantly lower mean craving across cue exposure trials at the medication-free 24-hour follow-up (d = -0.42, p = 0.046). There were no serious adverse events; however, side effects such as headache and dizziness occurred more frequently in the isradipine group. The findings of the current study support follow-up clinical trials that specifically test the efficacy of isradipine-augmented VR-CET for reducing smoking relapse rates after an initial quit attempt. clinicaltrials.gov: NCT03083353.

Dopamine signaling in nucleus accumbens is essential for cocaine reward. Interestingly, imaging studies have reported blunted dopamine increases in striatum (assessed as reduced binding of [ 11 C]raclopride to D 2 /D 3 receptors) in detoxified cocaine abusers. Here, we evaluate whether the blunted dopamine response reflected the effects of detoxification and the lack of cocaine-cues during stimulant exposure. For this purpose we studied 62 participants (43 non-detoxified cocaine abusers and 19 controls) using positron emission tomography and [ 11 C]raclopride (radioligand sensitive to endogenous dopamine) to measure dopamine increases induced by intravenous methylphenidate and in 24 of the cocaine abusers, we also compared dopamine increases when methylphenidate was administered concomitantly with a cocaine cue-video versus a neutral-video. In controls, methylphenidate increased dopamine in dorsal (effect size 1.4; P <0.001) and ventral striatum (location of accumbens) (effect size 0.89; P <0.001), but in cocaine abusers methylphenidate’s effects did not differ from placebo and were similar whether cocaine-cues were present or not. In cocaine abusers despite the markedly attenuated dopaminergic effects, the methylphenidate-induced changes in ventral striatum were associated with intense drug craving. Our findings are consistent with markedly reduced signaling through D 2 receptors during intoxication in active cocaine abusers regardless of cues exposure, which might contribute to compulsive drug use.

Objective This study aims to evaluate the effectiveness of virtual reality‐based aversion therapy in reducing craving, alleviating depression, and improving self‐efficacy in patients with substance use disorders undergoing methadone maintenance therapy. Methods The research was conducted as an interventional clinical trial involving 90 participants aged 25 to 55 years from outpatient treatment centers. The participants were randomly assigned to one of three groups: a group that received virtual reality‐based aversion therapy combined with methadone, a group that received psychological counseling combined with methadone, and a group that received methadone only. Results The findings revealed significant differences between the groups' means for depression (F = 19.652, p = 0.000), self‐efficacy (F = 33.956, p = 0.000), and craving (F = 65.445, p = 0.000 for desire and intent to use substances; F = 45.931, p = 0.000 for craving and negative reinforcement; F = 76.202, p = 0.000 for pleasure and intensity of lack of control). Specifically, virtual reality‐based aversion therapy significantly reduced the desire and intent to use substances, craving and negative reinforcement, and pleasure and intensity of lack of control compared to both psychological counseling and control groups. It also significantly reduced depression and enhanced self‐efficacy compared to both psychological counseling and control groups. This therapy, implemented through Python programming in a virtual reality environment with interactive and controlled simulations, facilitated gradual exposure to negative stimuli, cognitive restructuring, and the reinforcement of positive behaviors. Conclusion The results underscore the high potential of virtual reality–based aversion therapy to improve the effectiveness and quality of substance abuse treatment. This study emphasizes the necessity of further research in this field to improve therapeutic interventions and presents virtual reality‐based aversion therapy as an innovative, complementary, or alternative approach to substance use treatment. This study demonstrated that VR‐based aversion therapy combined with methadone treatment significantly reduced cravings, depression, and the desire to use substances while enhancing self‐efficacy

RationaleFemale cigarette smokers tend to show greater cessation failure compared with males. Variables that contribute to the maintenance of smoking, including stress and craving, may differentially impact male and female smokers. Novel pharmacotherapies, such as oxytocin, may attenuate stress reactivity and craving in smokers, but work in this area is limited.ObjectivesThis study assessed the influence of gender and oxytocin on stress reactivity, craving, and smoking in a randomized, placebo-controlled laboratory relapse paradigm.MethodsMale and female adult cigarette smokers (ages 18–45) were enrolled (women oversampled 2:1) and completed a laboratory session, in which intranasal oxytocin or placebo was administered followed by a laboratory social stress task. The role of gender and oxytocin were assessed on measures of stress reactivity, cigarette craving, latency to smoke in a resistance task, subjective responses to smoking, and ad-libitum smoking.ResultsParticipants (N = 144) had a mean age of 31 were 63% female and 56% White. Following stress induction, female smokers evidenced greater subjective stress than males, though males demonstrated greater neuroendocrine reactivity and smoking intensity than females. No gender differences were demonstrated for craving. Oxytocin did not attenuate any aspect of stress reactivity, craving, smoking, or subjective responses to smoking compared with placebo.ConclusionsGender differences in stress reactivity were shown in the hypothesized direction, but oxytocin appeared to exert little impact on subjective or behavioral metrics. Results highlight the complex relationship between gender, stress, and smoking, as well as the implications for oxytocin as a potential pharmacotherapy for smoking cessation.

RationaleAlcohol use disorder is a common and devastating mental illness for which satisfactory treatments are still lacking. Nalmefene, as an opioid receptor modulator, could pharmacologically support the reduction of drinking by reducing the (anticipated) rewarding effects of alcohol and expanding the range of treatment options. It has been hypothesized that nalmefene acts via an indirect modulation of the mesolimbic reward system. So far, only a few imaging findings on the neuronal response to nalmefene are available.ObjectivesWe tested the effect of a single dose of 18 mg nalmefene on neuronal cue-reactivity in the ventral and dorsal striatum and subjective craving.MethodsEighteen non-treatment-seeking participants with alcohol use disorder (67% male, M = 50.3 ± 13.9 years) with a current high-risk drinking level (M = 76.9 ± 52 g of pure alcohol per day) were investigated using a cue-reactivity task during functional magnetic resonance imaging (fMRI) in a double-blind, placebo-controlled, cross-over study/design. In addition, self-reported craving was assessed before and after exposure to alcohol cues.ResultsAn a priori defined region of interest (ROI) analysis of fMRI data from 15 participants revealed that nalmefene reduced alcohol cue-reactivity in the ventral, but not the dorsal striatum. Additionally, the subjective craving was significantly reduced after the cue-reactivity task under nalmefene compared to placebo.ConclusionIn the present study, reduced craving and cue-reactivity to alcohol stimuli in the ventral striatum by nalmefene indicates a potential anti-craving effect of this drug via attenuation of neural alcohol cue-reactivity.

Rationale Exposure to alcohol-related cues leads to increased alcohol consumption, and this may be partially attributable to momentarily impaired impulse control. Objectives We investigated if exposure to alcohol cues would impair inhibitory control and if the extent of this impairment would partially mediate the effect of alcohol cues on subsequent voluntary alcohol consumption. Methods We recruited 81 heavy drinkers (50 female) who completed baseline measures of inhibitory control (stop-signal task) and subjective craving before random allocation to an alcohol cue exposure or control group. The alcohol cue exposure group then completed a second stop-signal task (with embedded alcohol cues) with concurrent exposure to olfactory alcohol cues, in an alcohol context. The control group completed a second stop-signal task (with embedded water cues), accompanied by exposure to water cues, in a neutral context. Then, subjective craving and ad libitum alcohol consumption were measured in all participants. Results Inhibitory control worsened (compared to baseline) to a greater extent in the alcohol cue exposure group compared to the control group. Craving and ad libitum alcohol consumption were elevated in the alcohol cue exposure group compared to the control group, although the group difference in alcohol consumption fell short of statistical significance. In support of our hypotheses, multiple mediation analyses demonstrated that elevated ad libitum alcohol consumption following alcohol cue exposure was partially mediated by both impaired inhibitory control and increased craving. Conclusions These findings suggest that state fluctuations in inhibitory control are a potential mechanism through which alcohol cues increase drinking behaviour.

RationaleAttentional bias toward drug-related stimuli is a feature of drug addiction that is linked to craving and drug-seeking behavior.Objectives/methodAn attentional bias modification (ABM) program was tested in 42 methamphetamine-dependent clients (DSM-IV criteria) receiving residential treatment for their drug use. Participants were randomly assigned to one of two groups (N = 21 each), receiving 12 sessions of either computerized ABM training (designed to train attention away from methamphetamine stimuli 100% of the time) or an attentional control condition (designed to train attention away from methamphetamine stimuli 50% of the time). Outcome measures included attentional bias to methamphetamine-related stimuli on a probe detection task, self-reported craving, and preferences to view methamphetamine-related images on a Simulated Drug Choice Task. A subset of participants (N = 17) also underwent fMRI in a cue-induced craving paradigm.ResultsPoor split-half reliability was observed for the probe detection task. Using this task, attentional bias toward methamphetamine-related stimuli was greater after training than at baseline, irrespective of group (p = 0.037). Spontaneous and cue-induced methamphetamine craving diminished with time (ps < 0.01), but ABM training did not influence these effects (group by time interactions, ps > 0.05). ABM training did not influence selection of methamphetamine-related pictures in the Simulated Drug Choice task (p > 0.05). In the fMRI assessment, cue-induced activation in the ventromedial prefrontal cortex was reduced over time, without an effect of ABM training.ConclusionsABM training did not improve several clinically relevant variables in treatment-seeking methamphetamine users. Additional research is needed to improve the measurement of attentional bias.

Blockade of corticotropin-releasing factor receptor 1 (CRF1) suppresses stress-induced alcohol seeking in rodents, but clinical translation remains. Here, we first showed that the CRF1 antagonist verucerfont potently blocks hypothalamic-pituitary adrenal (HPA) axis activation in adrenalectomized rats. We then evaluated verucerfont for its ability to block HPA axis activation and reduce stress-induced alcohol craving in alcohol-dependent patients. Anxious, alcohol-dependent women (age 21-65 years, n=39) were admitted to the NIH Clinical Center and completed withdrawal treatment before enrollment if needed. One-week single-blind placebo was followed by randomized double-blind verucerfont (350 mg per day) or placebo for 3 weeks. Verucerfont effects on the HPA axis were evaluated using the dexamethasone-CRF test. Craving was evaluated using two established protocols, one that combines a social stressor with physical alcohol cue exposure, and one that uses guided imagery to present personalized stress, alcohol, or neutral stimuli. An fMRI session examined brain responses to negative affective stimuli and alcohol cues. In contrast to our recent observations with another CRF1 antagonist, pexacerfont, verucerfont potently blocked the HPA axis response to the dexamethasone-CRF test, but left alcohol craving unaffected. Right amygdala responses to negative affective stimuli were significantly attenuated by verucerfont, but responses to alcohol-associated stimuli were increased in some brain regions, including left insula. Discontinuation rates were significantly higher in the verucerfont group. Our findings provide the first translational evidence that CRF1 antagonists with slow receptor dissociation kinetics may have increased efficacy to dampen HPA axis responses. The findings do not support a clinical efficacy of CRF1 blockade in stress-induced alcohol craving and relapse.

Insula responses to drug cues are correlated with cravings, and lesions in this area reduce nicotine seeking. Here, we investigated the potential efficacy of repetitive transcranial magnetic stimulation (rTMS) targeting the insula in alcohol addiction. Treatment-seeking alcohol-dependent patients (Diagnostic and Statistical Manual of Mental Disorder, Fourth Edition; N = 56) participated in this double-blind, sham-controlled, randomized trial. Participants received 10 Hz rTMS or sham using an H8 coil, 5 days a week for 3 weeks. Stimulation targeted insular cortex and overlaying regions bilaterally, while excluding anterior prefrontal areas. Craving and self-reported as well as biomarker-based drinking measures were collected at baseline, during treatment, and through 12 weeks. Resting-state magnetic resonance imaging (rsMRI) data were collected before and after treatment. Task-based MRI was used to probe brain correlates of reward processing, affective responses, and alcohol following completion of treatment. A marked overall decrease in craving and drinking measures was observed during treatment, but did not differ between rTMS or sham stimulation. Both groups equally increased their alcohol use following completion of treatment and through the 12-week follow-up. Analysis using seeds in the insula identified differences in resting-state connectivity between active and sham groups at completion of treatment, potentially indicating an ability of treatment to modify insula function. However, while each task robustly replicated brain responses established in the literature, no effects of rTMS were found. Collectively, this study does not support efficacy of rTMS targeting the insula in alcohol addiction.