A reverse translational study of PPAR-α agonist efficacy in human and rodent models relevant to alcohol use disorder.

Alcohol Use Disorder (AUD) is a chronic relapsing disorder affecting an estimated 283 million individuals worldwide, with substantial health and economic consequences. Peroxisome proliferator-activated receptors (PPARs), particularly PPAR-α and PPAR-γ, have shown promise in preclinical studies as potential therapeutic targets for AUD. In this human laboratory study, we aimed to translate preclinical findings on the PPAR-α agonist fenofibrate to a human population with current AUD. We hypothesized that, relative to placebo, fenofibrate at the highest FDA-approved dose of 145 mg/d would attenuate responsiveness to in vivo alcohol cues in the lab and reduce drinking under natural conditions. However, the results did not show significant differences in craving and alcohol consumption between the fenofibrate and placebo groups. Reverse translational studies in rodent models confirmed the lack of fenofibrate effect at human-equivalent doses. These findings suggest that inadequate translation of drug dose from rodents to humans may account for the lack of fenofibrate effects on alcohol craving and consumption in humans with AUD. The results highlight the need for new brain-penetrant PPAR-α agonists to adequately test the therapeutic potential of PPAR-α agonists for AUD, and the importance of reverse translational approaches and selection of human-equivalent doses in drug development.

Preclinical and clinical evidence for suppression of alcohol intake by apremilast.

Treatment options for alcohol use disorders (AUDs) have minimally advanced since 2004, while the annual deaths and economic toll have increased alarmingly. Phosphodiesterase type 4 (PDE4) is associated with alcohol and nicotine dependence. PDE4 inhibitors were identified as a potential AUD treatment using a bioinformatics approach. We prioritized a newer PDE4 inhibitor, apremilast, as ideal for repurposing (i.e., FDA approved for psoriasis, low incidence of adverse events, excellent safety profile) and tested it using multiple animal strains and models, as well as in a human phase IIa study. We found that apremilast reduced binge-like alcohol intake and behavioral measures of alcohol motivation in mouse models of genetic risk for drinking to intoxication. Apremilast also reduced excessive alcohol drinking in models of stress-facilitated drinking and alcohol dependence. Using site-directed drug infusions and electrophysiology, we uncovered that apremilast may act to lessen drinking in mice by increasing neural activity in the nucleus accumbens, a key brain region in the regulation of alcohol intake. Importantly, apremilast (90 mg/d) reduced excessive drinking in non-treatment-seeking individuals with AUD in a double-blind, placebo-controlled study. These results demonstrate that apremilast suppresses excessive alcohol drinking across the spectrum of AUD severity.

Gabapentin for the treatment of alcohol use disorder.

INTRODUCTION: Alcohol misuse is the fifth leading risk factor for premature death and disability worldwide. Fewer than 10% of afflicted Americans receive pharmacological treatment for alcohol use disorder. Gabapentin is a calcium channel GABAergic modulator that is widely used for pain. Studies showing reduced drinking and decreased craving and alcohol-related disturbances in sleep and affect in the months following alcohol cessation suggest therapeutic potential for alcohol use disorder. Areas covered: Human laboratory and clinical studies assessing gabapentin for alcohol use disorder are reviewed. Data were obtained by searching for English peer-reviewed articles on PubMed, reference lists of identified articles, and trials registered on clinicaltrials.gov. Additionally, the mechanism of action of gabapentin specific to alcohol use disorder, and studies of gabapentin for alcohol withdrawal and non-alcohol substance use disorders are summarized. Expert opinion: Alcohol use disorder represents a challenge and large, unmet medical need. Evidence from single-site studies lend support to the safety and efficacy of gabapentin as a novel treatment for alcohol use disorder, with unique benefits for alcohol-related insomnia and negative affect, relative to available treatments. Proprietary gabapentin delivery systems may open a path to pivotal trials and registration of gabapentin as a novel treatment for alcohol use disorder.

Gabapentin treatment for alcohol dependence: a randomized clinical trial.

IMPORTANCE: Approved medications for alcohol dependence are prescribed for less than 9% of US alcoholics. OBJECTIVE: To determine if gabapentin, a widely prescribed generic calcium channel/γ-aminobutyric acid-modulating medication, increases rates of sustained abstinence and no heavy drinking and decreases alcohol-related insomnia, dysphoria, and craving, in a dose-dependent manner. DESIGN, PARTICIPANTS AND SETTING: A 12-week, double-blind, placebo-controlled, randomized dose-ranging trial of 150 men and women older than 18 years with current alcohol dependence, conducted from 2004 through 2010 at a single-site, outpatient clinical research facility adjoining a general medical hospital. INTERVENTIONS: Oral gabapentin (dosages of 0 [placebo], 900 mg, or 1800 mg/d) and concomitant manual-guided counseling. MAIN OUTCOMES AND MEASURES: Rates of complete abstinence and no heavy drinking (coprimary) and changes in mood, sleep, and craving (secondary) over the 12-week study. RESULTS Gabapentin significantly improved the rates of abstinence and no heavy drinking. The abstinence rate was 4.1% (95% CI, 1.1%-13.7%) in the placebo group, 11.1% (95% CI, 5.2%-22.2%) in the 900-mg group, and 17.0% (95% CI, 8.9%-30.1%) in the 1800-mg group (P = .04 for linear dose effect; number needed to treat [NNT] = 8 for 1800 mg). The no heavy drinking rate was 22.5% (95% CI, 13.6%-37.2%) in the placebo group, 29.6% (95% CI, 19.1%-42.8%) in the 900-mg group, and 44.7% (95% CI, 31.4%-58.8%) in the 1800-mg group (P = .02 for linear dose effect; NNT = 5 for 1800 mg). Similar linear dose effects were obtained with measures of mood (F2 = 7.37; P = .001), sleep (F2 = 136; P < .001), and craving (F2 = 3.56; P = .03). There were no serious drug-related adverse events, and terminations owing to adverse events (9 of 150 participants), time in the study (mean [SD], 9.1 [3.8] weeks), and rate of study completion (85 of 150 participants) did not differ among groups. CONCLUSIONS AND RELEVANCE: Gabapentin (particularly the 1800-mg dosage) was effective in treating alcohol dependence and relapse-related symptoms of insomnia, dysphoria, and craving, with a favorable safety profile. Increased implementation of pharmacological treatment of alcohol dependence in primary care may be a major benefit of gabapentin as a treatment option for alcohol dependence. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00391716.

A proof-of-concept randomized controlled study of gabapentin: effects on cannabis use, withdrawal and executive function deficits in cannabis-dependent adults.

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.

Craving in response to stress induction in a human laboratory paradigm predicts treatment outcome in alcohol-dependent individuals.

RATIONALE: 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. OBJECTIVE: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Mood disorders and substance use disorder: a complex comorbidity.

Mood disorders, including depression and bipolar disorders, are the most common psychiatric comorbidities among patients with substance use disorders. Treating patients' co-occurring mood disorders may reduce their substance craving and taking and enhance their overall outcomes. A methodical, staged screening and assessment can ease the diagnostic challenge of distinguishing symptoms of affective disorders from manifestations of substance intoxication and withdrawal. Treatment should maximize the use of psychotherapeutic interventions and give first consideration to medications proven effective in the context of co-occurring substance abuse. Expanded communication and collaboration between substance abuse and mental health providers is crucial to improving outcomes for patients with these complex, difficult co-occurring disorders.

Combating substance abuse with ibogaine: pre- and posttreatment recommendations and an example of successive model fitting analyses.

Ibogaine is an indole alkaloid derived from the root bark of the African shrub Tabernan the iboga and it has been used for many years as a medicinal and ceremonial agent in West Central Africa. Furthermore, both anecdotal observations and recent studies suggest that ibogaine alleviates withdrawal symptoms and reduces drug cravings. Although ibogaine articles typically include information bearing on the duration of drug abstinence following treatment, little if any attention is given to the psychological and environmental factors that might facilitate a positive treatment outcome. Hence, a major purpose of the present review is to suggest a number of theory-driven, pretreatment and posttreatment recommendations that have good potential for enhancing ibogaine's effectiveness. The second major purpose of this review is to demonstrate, through a reanalysis of previously published results, the utility of conducting successive model fitting analyses on ibogaine treatment data. Such analyses are useful for determining both the strength and form of the association between pre-ibogaine treatment variables and post-ibogaine treatment outcomes. Finally, in order to facilitate future quantitative reviews, the authors recommend that a minimum set of patient- and treatment-related variables be included in all ibogaine publications involving human participants.