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1.
Biol Psychiatry Glob Open Sci ; 4(6): 100368, 2024 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-39282655

RESUMEN

Background: Alcohol use disorder (AUD) is a chronic relapsing disorder characterized by alcohol seeking and consumption despite negative consequences. Despite the availability of multiple treatments, patients continue to exhibit high relapse rates. Thus, biomarkers that can identify patients at risk for heightened craving are urgently needed. Mounting preclinical and clinical evidence implicates perturbations in bioactive lipid signaling in the neurobiology of craving in AUD. We hypothesize that these lipids are potential biomarkers for predicting alcohol craving in patients with AUD. Methods: This study used archival deidentified clinical data and corresponding plasma specimens from 157 participants in 3 clinical studies of AUD. We evaluated plasma levels of 8 lipid species as predictors of craving in response to in vivo alcohol and affective cues during abstinence. Results: Participants were 109 men and 48 women who met DSM-5 criteria for severe AUD. We found that plasma levels of 12- and 15-HETE, 12/15-lipoxygenase-produced proinflammatory lipids, and palmitoylethanolamide, an anti-inflammatory fatty acid amide hydrolase-regulated lipid metabolite, were differentially correlated with alcohol craving during abstinence, predicting higher craving independent of demographics, alcohol use history, and multiple therapeutic treatments. Conclusions: Our findings highlight the promise of these lipid metabolites as biomarkers of heightened alcohol craving. The results open a novel opportunity for further research and clinical evaluation of these biomarkers to optimize existing treatments and develop new therapeutics for AUD.


Alcohol use disorder (AUD) is a chronic relapsing disorder characterized by the compulsion to seek out and consume alcohol regardless of negative consequences. Despite the availability of multiple treatment options, patients continue to exhibit high relapse rates due in part to craving during abstinence. The current study evaluated the relationship between plasma lipids and alcohol craving during abstinence to determine whether we could predict vulnerable patients independent of treatment approach and history of alcohol use.

2.
Neurobiol Stress ; 29: 100604, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38292518

RESUMEN

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.

3.
J Clin Invest ; 133(6)2023 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-36656645

RESUMEN

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.


Asunto(s)
Alcoholismo , Inhibidores de Fosfodiesterasa 4 , Psoriasis , Humanos , Ratones , Animales , Talidomida/farmacología , Inhibidores de Fosfodiesterasa 4/farmacología , Inhibidores de Fosfodiesterasa 4/uso terapéutico , Psoriasis/tratamiento farmacológico , Etanol , Consumo de Bebidas Alcohólicas/genética
4.
Expert Opin Investig Drugs ; 27(1): 113-124, 2018 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-29241365

RESUMEN

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.


Asunto(s)
Consumo de Bebidas Alcohólicas/prevención & control , Alcoholismo/tratamiento farmacológico , Aminas/uso terapéutico , Ácidos Ciclohexanocarboxílicos/uso terapéutico , Ácido gamma-Aminobutírico/uso terapéutico , Alcoholismo/fisiopatología , Aminas/efectos adversos , Aminas/farmacología , Animales , Bloqueadores de los Canales de Calcio/efectos adversos , Bloqueadores de los Canales de Calcio/farmacología , Bloqueadores de los Canales de Calcio/uso terapéutico , Ácidos Ciclohexanocarboxílicos/efectos adversos , Ácidos Ciclohexanocarboxílicos/farmacología , Gabapentina , Humanos , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , Trastornos del Inicio y del Mantenimiento del Sueño/etiología , Síndrome de Abstinencia a Sustancias/tratamiento farmacológico , Ácido gamma-Aminobutírico/efectos adversos , Ácido gamma-Aminobutírico/farmacología
5.
JAMA Intern Med ; 174(1): 70-7, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-24190578

RESUMEN

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.


Asunto(s)
Alcoholismo/tratamiento farmacológico , Aminas/uso terapéutico , Ácidos Ciclohexanocarboxílicos/uso terapéutico , Moduladores del GABA/uso terapéutico , Ácido gamma-Aminobutírico/uso terapéutico , Adulto , Abstinencia de Alcohol , Depresores del Sistema Nervioso Central/efectos adversos , Método Doble Ciego , Etanol/efectos adversos , Femenino , Gabapentina , Humanos , Masculino , Persona de Mediana Edad , Síndrome de Abstinencia a Sustancias/etiología , Síndrome de Abstinencia a Sustancias/prevención & control , Resultado del Tratamiento
6.
Neuropsychopharmacology ; 37(7): 1689-98, 2012 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-22373942

RESUMEN

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.


Asunto(s)
Aminas/uso terapéutico , Bloqueadores de los Canales de Calcio/uso terapéutico , Ácidos Ciclohexanocarboxílicos/uso terapéutico , Función Ejecutiva/efectos de los fármacos , Abuso de Marihuana/terapia , Síndrome de Abstinencia a Sustancias/terapia , Ácido gamma-Aminobutírico/uso terapéutico , Adolescente , Adulto , Aminas/farmacología , Bloqueadores de los Canales de Calcio/farmacología , Cannabis/efectos adversos , Consejo , Ácidos Ciclohexanocarboxílicos/farmacología , Método Doble Ciego , Femenino , Gabapentina , Humanos , Masculino , Abuso de Marihuana/tratamiento farmacológico , Abuso de Marihuana/psicología , Persona de Mediana Edad , Síndrome de Abstinencia a Sustancias/tratamiento farmacológico , Síndrome de Abstinencia a Sustancias/psicología , Resultado del Tratamiento , Ácido gamma-Aminobutírico/farmacología
7.
Psychopharmacology (Berl) ; 218(1): 121-9, 2011 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-21607563

RESUMEN

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.


Asunto(s)
Consumo de Bebidas Alcohólicas/psicología , Alcoholismo/psicología , Hidrocortisona/metabolismo , Estrés Psicológico/complicaciones , Adulto , Alcoholismo/rehabilitación , Atención Ambulatoria , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Recurrencia , Saliva/química , Templanza , Factores de Tiempo , Adulto Joven
8.
Sci Pract Perspect ; 3(1): 13-21, 2005 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-18552741

RESUMEN

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.


Asunto(s)
Trastornos del Humor/diagnóstico , Trastornos del Humor/terapia , Trastornos Relacionados con Sustancias/diagnóstico , Trastornos Relacionados con Sustancias/terapia , Terapia Cognitivo-Conductual , Comorbilidad , Diagnóstico Diferencial , Humanos , Trastornos del Humor/tratamiento farmacológico , Trastornos del Humor/epidemiología , Psicotrópicos/uso terapéutico , Grupos de Autoayuda , Trastornos Relacionados con Sustancias/tratamiento farmacológico , Trastornos Relacionados con Sustancias/epidemiología
9.
J Psychoactive Drugs ; 36(2): 191-9, 2004 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-15369200

RESUMEN

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.


Asunto(s)
Ibogaína/uso terapéutico , Modelos Teóricos , Trastornos Relacionados con Sustancias/tratamiento farmacológico , Adulto , Femenino , Humanos , Modelos Lineales , Masculino
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