•Early drug development for AUD focused on blocking the motivation to seek alcohol.•A new focus is reversing motivational dysregulation associated with protracted abstinence.•Validated animal models provide targets to normalize brain stress/reward systems in AUD.•Human lab models of protracted abstinence provide POC screening of potential drugs for AUD.The identification of different stages within the alcohol use disorder (AUD) cycle that are linked to neurocircuitry changes in pathophysiology associated with the negative emotional states of abstinence has provided a view of medication development for AUD that emphasizes changes in the brain reward and stress systems. Alcohol use disorder can be defined as a chronic relapsing disorder that involves compulsive alcohol seeking and taking, loss of control over alcohol intake, and emergence of a negative emotional state during abstinence. The focus of early medications development was to block the motivation to seek alcohol in the binge/intoxication stage. More recent work has focused on reversing the motivational dysregulations associated with the withdrawal/negative affect and preoccupation/anticipation stages during protracted abstinence. Advances in our understanding of the neurocircuitry and neuropharmacological mechanisms that are involved in the development and maintenance of the withdrawal/negative affect stage using validated animal models have provided viable targets for future medications. Another major advance has been proof-of-concept testing of potential therapeutics and clinical validation of relevant pharmacological targets using human laboratory models of protracted abstinence. This review focuses on future targets for medication development associated with reversal of the loss of reward function and gain in brain stress function that drive negative reinforcement in the withdrawal/negative affect stage of addiction. Basic research has identified novel neurobiological targets associated with the withdrawal/negative affect stage and preoccupation/anticipation stage, with a focus on neuroadaptive changes within the extended amygdala that account for the transition to dependence and vulnerability to relapse.This article is part of the Special Issue entitled “Alcoholism”.Download high-res image (291KB)Download full-size image

There are no FDA-approved pharmacotherapies for cannabis dependence. Cannabis is the most widely used illicit drug in the world, and patients seeking treatment for primary cannabis dependence represent 25% of all substance use admissions. We conducted a phase IIa proof-of-concept pilot study to examine the safety and efficacy of a calcium channel/GABA modulating drug, gabapentin, for the treatment of cannabis dependence. A 12-week, randomized, double-blind, placebo-controlled clinical trial was conducted in 50 unpaid treatment-seeking male and female outpatients, aged 18–65 years, diagnosed with current cannabis dependence. Subjects received either gabapentin (1200 mg/day) or matched placebo. Manual-guided, abstinence-oriented individual counseling was provided weekly to all participants. Cannabis use was measured by weekly urine toxicology and by self-report using the Timeline Followback Interview. Cannabis withdrawal symptoms were assessed using the Marijuana Withdrawal Checklist. Executive function was measured using subtests from the Delis–Kaplan Executive Function System. Relative to placebo, gabapentin significantly reduced cannabis use as measured both by urine toxicology (p=0.001) and by the Timeline Followback Interview (p=0.004), and significantly decreased withdrawal symptoms as measured by the Marijuana Withdrawal Checklist (p<0.001). Gabapentin was also associated with significantly greater improvement in overall performance on tests of executive function (p=0.029). This POC pilot study provides preliminary support for the safety and efficacy of gabapentin for treatment of cannabis dependence that merits further study, and provides an alternative conceptual framework for treatment of addiction aimed at restoring homeostasis in brain stress systems that are dysregulated in drug dependence and withdrawal.

Alcohol dependence is associated with high rates of recidivism. Stress has been shown to increase alcohol craving in alcohol-dependent individuals, but the association between stress-induced craving and alcoholism treatment outcome is not well understood.The aim of the present study was to examine the relationship between strength of stress-induced alcohol craving in the human laboratory and subsequent drinking in a cohort of treatment-seeking, alcohol-dependent adults.This is a prospective study assessing stress-induced craving in the lab and subsequent treatment outcomes in alcohol-dependent subjects enrolled in a 12-week outpatient study. Stress was induced using a previously developed, individualized, audio recorded stress script and validated with objective (salivary cortisol) and subjective measures of distress. In vivo craving for alcohol was measured pre- and post-challenge using VAS.Subjects were 28 (16 male, 12 female) alcohol-dependent outpatients. Greater stress-induced craving was associated with a blunted salivary cortisol response, significantly shorter time to alcohol relapse, higher mean drinks per week, fewer percent days abstinent, and lower rates of complete abstinence over the study duration (all p's < 0.05). Conversely, no demographic or baseline variables were significant predictors of any outcome variable.These results suggest that greater stress-related increases in alcohol craving are associated with poorer alcohol treatment outcomes. The findings support the use of stress-induced craving as a predictor of alcohol relapse propensity. Furthermore, treatments that address high stress levels and the associated high levels of alcohol craving are likely to improve treatment outcomes in alcohol dependence.

Laboratory paradigms are useful for investigating mechanisms of human alcohol cue reactivity in a highly controlled environment. A number of studies have examined the effects of beverage exposure or negative affective stimuli on cue reactivity independently, but only a few have reported on interaction effects between beverage cue and affective stimuli, and none have evaluated the effects of positive stimuli on beverage cue reactivity.To assess independent and interactive effects of both positive and negative affective stimuli and beverage cue on psychophysiological and subjective measures of reactivity in alcohol dependence.A total of 47 non-treatment-seeking paid volunteers with current alcohol dependence participated in a within-subjects trial where each was exposed to a standardized set of pleasant, neutral, or unpleasant visual stimuli followed by alcohol or water cues. Psychophysiological cue-reactivity measures were obtained during beverage presentation, and subjective reactivity measures were taken directly following beverage presentation.Mixed-effect models revealed a significant main effect of beverage and positive (but not negative) affective stimuli on subjective strength of craving and significant main effects of both positive and negative affective stimuli on ratings of emotionality. Despite the power to detect relatively small interaction effects, no significant interactions were observed between affect and beverage conditions on any reactivity measure. A key finding of this study is that positive affective stimuli commonly associated with drinking situations can induce craving in the absence of alcohol cues. Main effects of beverage cue replicated results from previous studies. Beverage and affective cues showed no interaction effects.