PPARγ activation by pioglitazone does not suppress cravings for alcohol, and is associated with a risk of myopathy in treatment seeking alcohol dependent patients: a randomized controlled proof of principle study.

RATIONALE: Proinflammatory 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. OBJECTIVES: We conducted a double-blind, placebo-controlled mechanistic proof of principle study in alcohol-dependent inpatients to investigate the effect of pioglitazone on alcohol craving. METHODS: Participants 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. RESULTS: The 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. CONCLUSIONS: Both safety and efficacy biomarker data suggest that pioglitazone lacks potential as a medication for the treatment of alcohol dependence. CLINICAL TRIAL REGISTRATION: NCT01631630.

Stress vulnerability and alcohol use and consequences: From human laboratory studies to clinical outcomes.

It is well known that vulnerability to stress is a risk factor for alcohol use disorder (AUD). Chronic alcohol use can result in neuroadaptations in cortico-striatal pathways and hypothalamic pituitary adrenal (HPA) axis function that are manifested in altered behavioral and cognitive control functions contributing to alcohol craving, compulsive motivation, consumption, and consequences. This symposium brings together studies utilizing novel approaches to help improve our understanding of stress - past, acute, and chronic - on alcohol seeking and consumption and related outcomes using a combination of human laboratory models, neuroimaging, and clinical measures. Examining factors that determine vulnerability as well as resilience to stress are of particular interest in the study of AUD because, in addition to increasing our understanding of the risk factors for AUD, such knowledge can be used to develop more effective treatments. Dr. Stangl presented a novel human experimental model that demonstrates, for the first time, stress-induced increases in alcohol self-administration in binge drinkers using a guided imagery paradigm combined with intravenous alcohol self-administration (IV-ASA). Dr. Blaine presented data demonstrating that glucocorticoid response to stress drives compulsive alcohol motivation and intake in binge/heavy drinkers. Dr. Plawecki presented data examining sex differences in the effect of two distinct stress paradigms - mood induction and abstinence - on IV-ASA in moderate drinkers. Dr. Schwandt presented clinical data providing a new perspective on the relationship between childhood trauma and AUD by suggesting possible underlying mechanisms that confer resilience, rather than vulnerability, to severe early life stress exposure.

FAAH Gene Variation Moderates Stress Response and Symptom Severity in Patients with Posttraumatic Stress Disorder and Comorbid Alcohol Dependence.

BACKGROUND: A common single nucleotide polymorphism (C385A) in the human fatty acid amide hydrolase (FAAH) gene has been associated with decreased distress responses in healthy volunteers, but its role in psychiatric disorders remains unknown. Here, we obtained genotypes and carried out a secondary analysis of subjects from a trial of comorbid posttraumatic stress disorder (PTSD) and alcohol dependence (AD). We evaluated the effects of C385A variation on behavioral and biochemical biomarkers of distress responses. METHODS: Forty-nine patients with PTSD and AD were admitted for 4 weeks to an experimental medicine unit at the National Institutes of Health Clinical Center. Following detoxification, stress reactivity and peripheral endocannabinoid (eCB) levels were assessed in response to a challenge session using personalized auditory guided imagery. Over the course of the study, subjects were also evaluated for changes in PTSD symptom severity. RESULTS: FAAH C385A allele carriers showed a marked increase in serum anandamide levels at baseline and throughout the stress challenge procedure compared with C allele homozygotes, while levels of eCBs primarily metabolized through other enzymatic activity, such as 2-arachidonoylglycerol, did not differ between genotype groups. FAAH C385A carriers also had decreased subjective anxiety responses to the stress challenge. Similar effects of FAAH C385A genotype were found at the level of clinical PTSD symptom severity, in particular in the arousal domain. CONCLUSIONS: This is to our knowledge the first study showing that FAAH C385A variation modulates stress responses in subjects with disorders characterized by increased stress reactivity. These findings point to the eCB pathway as a promising target for future antistress therapeutics.

The CRF1 Antagonist Verucerfont in Anxious Alcohol-Dependent Women: Translation of Neuroendocrine, But not of Anti-Craving Effects.

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.

Methods for inducing alcohol craving in individuals with co-morbid alcohol dependence and posttraumatic stress disorder: behavioral and physiological outcomes.

Alcohol addiction is a chronic relapsing disorder that presents a substantial public health problem, and is frequently co-morbid with posttraumatic stress disorder (PTSD). Craving for alcohol is a predictor of relapse to alcohol use, and is triggered by cues associated with alcohol and trauma. Identification of reliable and valid laboratory methods for craving induction is an important objective for alcoholism and PTSD research. The present study compares two methods for induction of craving via stress and alcohol cues in individuals with co-morbid alcohol dependence (AD) and PTSD: the combined Trier social stress test and cue reactivity paradigm (Trier/CR), and a guided imagery (Scripts) paradigm. Outcomes include self-reported measures of craving, stress and anxiety as well as endocrine measures. Subjects were 52 individuals diagnosed with co-morbid AD and PTSD seeking treatment at the National Institute on Alcohol Abuse and Alcoholism inpatient research facility. They participated in a 4-week inpatient study of the efficacy of a neurokinin 1 antagonist to treat co-morbid AD and PTSD, and which included the two challenge procedures. Both the Trier/CR and Scripts induced craving for alcohol, as well as elevated levels of subjective distress and anxiety. The Trier/CR yielded significant increases in adrenocorticotropic hormone and cortisol, while the Scripts did not. Both paradigms are effective laboratory means of inducing craving for alcohol. Further research is warranted to better understand the mechanisms behind craving induced by stress versus alcohol cues, as well as to understand the impact of co-morbid PTSD and AD on craving.